key: cord-0928809-3mjwd657
authors: Mahajan, Supreeti; Choudhary, Shweta; Kumar, Pravindra; Tomar, Shailly
title: Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens
date: 2021-08-08
journal: Bioorg Med Chem
DOI: 10.1016/j.bmc.2021.116356
sha: d7f253c6a787fceb5845c8fa33af0234c32f73a5
doc_id: 928809
cord_uid: 3mjwd657

The ongoing COVID-19 pandemic, periodic recurrence of viral infections, and the emergence of challenging variants has created an urgent need of alternative therapeutic approaches to combat the spread of viral infections, failing to which may pose a greater risk to mankind in future. Resilience against antiviral drugs or fast evolutionary rate of viruses is stressing the scientific community to identify new therapeutic approaches for timely control of disease. Host metabolic pathways are exquisite reservoir of energy to viruses and contribute a diverse array of functions for successful replication and pathogenesis of virus. Targeting the host factors rather than viral enzymes to cease viral infection, has emerged as an alternative antiviral strategy. This approach offers advantage in terms of increased threshold to viral resistance and can provide broad-spectrum antiviral action against different viruses. The article here provides substantial review of literature illuminating the host factors and molecular mechanisms involved in innate/adaptive responses to viral infection, hijacking of signalling pathways by viruses and the intracellular metabolic pathways required for viral replication. Host-targeted drugs acting on the pathways usurped by viruses are also addressed in this study. Host-directed antiviral therapeutics might prove to be a rewarding approach in controlling the unprecedented spread of viral infection, however the probability of cellular side effects or cytotoxicity on host cell should not be ignored at the time of clinical investigations.

terms of the host traits hijacked by them for downregulating antiviral response and viral dependency on host metabolic pathways (Lipid synthesis/polyamine metabolism/glucose metabolism). The virus life cycle begins with the attachment of viral glycoproteins to the host cell receptor, and entry into host cell via receptor-mediated endocytosis. 14, 25, 26 Following entry, open reading frame (ORF) of viral genome is translated to generate polypeptide of nsPs. 14 Viral proteases, such as nsP2 of CHIKV, 3C-like protease (3CLpro) and papain like protease (PLpro) of SARS-CoV and SARS-CoV-2, NS2B/NS3 protease of DENV etc. further cleaves polypeptide into individual nsPs by autoproteolytic activity. 3, 14, 27, 28 These nsPs further aids in replication (RdRp), capping (methyltransferase (MTase), and guanylyltransferase (GTase) activities of viral genome. 29 The nsPs forms the replication-transcription complexes (RTC), essential for carrying out the replication of viral genome. Through a negative-sense RNA intermediate, the genomic RNA is transcribed and translated to form the structural and accessory proteins. 14, 27, 30 For flaviviruses, the genomic RNA is initially transcribed to form negative-sense RNA resulting in a dsRNA replication intermediate which acts as a template for synthesis of large number of capped +ssRNA viral genomes. These newly generated viral genome further helps in translation of viral proteins and generation of sfRNA (subgenomic flaviviral RNA). 31 For coronaviruses and flaviviruses, translated structural proteins translocates through endoplasmic reticulum (ER) and golgi body to encapsidate the newly produced genomic RNA and to bud off the virions by exocytosis. 27, 32 E1 and E2 envelope proteins of alphaviruses undergoes translocation through ER-to-Golgi complex for processing and maturation of glycoproteins, whereas the genomic RNA gets surrounded by capsid protein in the cytoplasm itself. Ultimately the capsid encapsulated genomic RNA bud out through the cell membrane after acquiring the lipid bilayer envelope composed of E1 and E2 proteins. 33, 34 The survival of virus in the host cells depends upon the host factors to render the infected cell amenable for the viral genome replication, and therefore, identification of these host-viral interactions is fundamental for development of host-targeted antiviral drugs. Some of the key approaches used for identifying host-viral interactions are RNAi-based methods 23, 35 , drug combination approach 36 , transcriptome and proteomic analysis of virus infected cells 37 , and CRISPR/Cas9 screens. 23, 38 Small interfering RNA screens are used for high-throughput screening of host factors required for replication and pathogenesis of viruses. 39, 40 Drug combination approach uses a suitable combination of drugs to target multiple host proteins and signalling enzymes that aids in viral pathogenesis. 36 CRISPR/Cas9 is an improved approach to identify exploitable host factors for the development of antivirals. 41 Major advantages of these approaches lie in the fact that the most of the drugs against host pathways are FDA approved for treatment of different diseases and can be instantly used to treat viral diseases (Table 1) . Moreover, the targets of such drugs are well characterised, validated and pose no or very little safety risks.

Several pioneering studies have identified important host proteins exploited by viruses for prolonging their survival such as Hepatitis C virus (HCV) depends on the vesicle-associated membrane protein-associated protein, 33-kDa human homologue (hVAP-33), and HIV exploits C-C chemokine receptor type 5 (CCR5) to facilitate its successful infection. 42, 43 Similarly, influenza virus also exploits host proteases and other important nuclear components to evade host antiviral responses and to successfully establish its infection. 44, 45, 46, 47 Focussing primarily on +ssRNA viruses, lipid biosynthesis pathway, glycolytic pathway, the stress-granule formation machinery, polyamine metabolism/catabolism, cytokine based inflammatory response, and the proteasome based ubiquitination/deubiquitination steps are the key targets exploited by viruses. 48, 49, 50, 51, 52 A majority of these factors are dispensable for the host cell but are highly essential for viruses to complete their life cycle.

This article highlights various approaches for upregulating host-mediated antiviral action against viruses to prevent replication of viruses, how host factors of different metabolic pathways assist viral replication, as well as progress and achievements in the field of antiviral drug development using these approaches. The cellular metabolism of the host cell is the power house for all required ATP (energy), biosynthetic building blocks and many other important molecules needed for replication of viruses. Viruses require an uninterrupted supply of all these essential building blocks from the host at various stages of their replication cycle. Besides nucleotides and amino acids, many viruses need constant supply of host's cellular fatty acids and lipids. +ssRNA viruses are known to remodel host membranes for their entry and genomic replication. 72 Recent research has highlighted that the host lipids, being major constituents of cellular membrane, plays crucial role in the replication of many +ssRNA viruses. 73 From viral entry, replication and translation of genome to assembly or budding of progeny virions, lipids from diverse lipid classes play significant role in viral life cycle to create an appropriate environment for thriving and surviving inside the host. Lipids are a large diverse group of non-polar and amphipathic molecules that are necessary for all cellular life forms. Lipids serve three basic cellular functions: firstly acts as building blocks of cellular membranes such as phospholipids, sterols, and sphingolipids. 15 Secondly, some lipids such as triacylglycerol and steryl ester, function as energy sources in the form of lipid droplets. 74 Thirdly, some lipids such as phosphatidic acid, sterols, sphingolipids, and glycerolipids serve as signalling molecules in multiple cellular pathways. 75 Apart from these, many host lipids are also essential for virus replication. Lipids are the structural constituents of all enveloped virions. Lipid membranes act as platforms for viral gene expression, replication, assembly, and protection of these processes from host defense system by compartmentalizing them. Interestingly, specific viruses have a preference for a particular membrane lipid composition on which they replicate. For doing so, viruses need to manipulate host lipid metabolism pathways to ensure the availability of lipids to complete their life cycle. Host cell membranes undergo a process called membrane bending and deformation, which give rise to distinct morphological structures such as small spherules, vesicles, membranous webs, and reticular layers for viral replication. Some common routes for lipid biosynthesis and inhibitors targeted in downstream steps are depicted in Figure 1 .

Alphaviruses acquire envelope during budding from plasma membrane and the lipid envelope also plays an essential role of mediating entry of virus into the host cell. For alphaviruses, the lipid composition of the viral envelope is highly significant for improving stability of viral genome and enhancing infectivity. Sphingolipids and cholesterol are essential components of host cell membranes liable for fusion of alphavirus envelope and for the viral exit. 76 Therefore, it could be a promising strategy to target host lipid synthesis pathways for inhibiting arthritogenic alphaviruses. Fatty acid synthase (FASN) is an important enzyme supporting de novo synthesis of long chain fatty acids and stearoyl-CoA desaturase (SCD1) enzyme and is imperative for their early desaturation. Both these enzymes are reported to play important role in the replication of Mayaro virus (MAYV) and CHIKV. 77 Moreover, host transcription factors such as liver X receptors (LXR α and LXR β) of lipid synthesis pathway are vital for intracellular cholesterol homeostasis. 78 On the other hand, flaviviruses such as HCV, DENV, and West Nile virus (WNV) stimulates the lipid biosynthesis pathway for their membrane formation. 79 Fatty acids, sphingolipids, sterols, triglycerides, and many other lipid compositions of the host are used by flaviviruses for the formation of envelope. Apart from envelope formation, composition of membrane also plays and important role for prompting viral infection. In DENV, acetyl-coenzyme A (AcCoA) is required for the generation of distinct membrane lipids. 80 A variant of selective autophagy known as lipophagy, transports lipids for oxidation. The lipids get accumulated in auto-phagosomes and are transported to mitochondria which produces energy, playing an important part in lipophagy, thus facilitating DENV replication. 81 Moreover, NADPH formed as a result of oxidation, uses a cofactor of FASN and thus, assists fatty acid synthesis that is exploited by DENV for its replication. 82 Flaviviruses exploits host cell in such a way that both fatty acid synthesis and lipophagy occur at the same time, in contrast to healthy cells. DENV and JEV also modulates cholesterol synthesis and trafficking which assists viral entry and replication. 83 Cholesterol increases the expression of Angiotensin converting enzyme 2 (ACE2) receptor and hence potentiates the interaction between ACE2 and spike protein of SARS-CoV-2. 84 Intriguingly coronaviruses such as SARS-CoV and SARS-CoV-2 seize host membranes to form double membrane vesicles (DMVs) for their genomic amplification. 85, 86 Cytosolic phospholipase A2α enzyme (cPLA2α), a lipid processing enzyme is crucial for DMV formation and replication of coronaviruses. 87

Targeting host cellular lipid metabolism by blocking lipid biosynthesis pathways could potentially be a promising antiviral strategy but may be restricted due to host cell toxicity. To overcome this, knowledge of the structural and functional details of the lipids, their role in viral replication, their origin sites, and the sites where they are trafficked to, are prerequisite for identifying antivirals. Rational design of host-targeted antivirals can be achieved by identifying and targeting lipids that are non-essential for host cell or by targeting steps in lipid synthesis and metabolism that are extremely sensitive to viruses rather than host cell. This will allow host-targeted antiviral strategies with a reasonable therapeutic window without globally affecting the host cell. In DENV, WNV and Zika virus (ZIKV), it has been demonstrated that treating the host cells with the chemical inhibitors suppressing fatty acid biosynthesis has resulted in reduction of viral load. 88 FASN, ATP citrate lyase (ACLY), Acetyl coenzyme A carboxylase (ACC) are key enzymes responsible for regulating fatty acid biosynthesis in eukaryotic host cells. Previously published literature has suggested that targeting ACC with chemical fatty acid biosynthesis inhibitors MEDICA 16 (3,3,14,14-tetramethylhexadecanedioic acid) and TOFA (5-(tetradecyloxy)-2-furoic acid) reduced replication of flaviviruses such as WNV and Usutu virus (USUV). 89 The mode of action of these compounds is to act by reducing levels of multiple cellular lipids such as sphingolipids, glycerophospholipids, and cholesterol. 89 Additionally, TOFA exhibit broad spectrum activity against both ZIKV (Flaviviridae) and semliki forest virus (SFV, Togaviridae) by blocking the enzyme ACC. 90 Moreover, inhibition of FASN and mevalonate diphosphate decarboxylase enzymes required for cholesterol biosynthesis, reduced DENV titer in host cells. 91 Cerulenin, an antibiotic and inhibitor of lipid biosynthesis, and orlistat, an anti-obesity drug, both displayed broad spectrum antiviral activity by blocking FASN enzyme in ZIKV, SFV, CHIKV, and MAYV respectively. 77 Inhibition of SCD1 enzyme activity by CAY10566 (a potent, orally bioavailable and selective inhibitor of SCD1) reduced in vitro replication of both CHIKV and MAYV. 77 Antidepressant drug, imipramine, interferes in the cholesterol trafficking, resulting in the reduction of CHIKV replication in human skin fibroblast cells. 92 Liver X receptors such as LXR α and LXR β are one of the many potential targets in host lipid pathway. LXR-623, the LXR β selective agonist, has been demonstrated to inhibit replication of CHIKV in human fibroblasts. 93 Specific role of lipids and inhibitors reported to target host lipid pathway are listed in Table 2 . In infected cells, many viruses rewire host cellular metabolism to enhance their genome replication for survival in host. 112 Reprogramming the host primary carbon metabolism cycle including glycolysis is one such aspect. 16, 113 The precise changes in host metabolism depends upon virus to virus within the same family or on the type of host cell and is context-dependent. In glycolysis, ATP and pyruvate are the major metabolites formed from glucose. 114 The final step in the glycolytic pathway is the conversion of PEP (2-phosphoenolpyruvate) to pyruvate and ATP in the presence pyruvate kinase ( Figure 2 ). 16, 113, 115 Stress glycolysis is also the major contributing source of essential metabolites for many biosynthetic pathways such as amino acids, lipids, and nucleic acids. 114 Apart from this, glycolytic machinery is also important for the activation of immune cells. 116 To receive quick ATP supply, many viruses enhance the upregulation of aerobic glycolytic mechanism as well as glucose uptake. 117

In DENV infection, a primary change occurs in central carbon metabolism that is glycolysis, where the consumption of glucose is increased along with upregulation of both glucose transporter 1 (GLUT1) and hexokinase II (HK-II) genes. 118 In order to meet viral metabolic requirements for completion of replication and life cycle, DENV activates glycolytic pathway. In healthy cells, glucose and glutamine serve as the primary carbon source and oxidation of glucose generates ATP via glycolysis in tricarboxylic acid (TCA) cycle ( Figure 2 ). 112 However, in human cytomegalovirus (HCMV) infected cells, glutamine instead of glucose is used as carbon source for ATP generation in TCA cycle. 119 An elevated glycolysis or glucose level is also necessary for SARS-CoV-2 replication and for SARS-COV-2 induced monocyte immune response. 120 Various SARS-CoV-2 inhibitors that are designed against host glycolytic pathway are fasentin, phloretin (GLUT 2 inhibitor), ritonavir (GLUT4 inhibitor), and silybin/silibinin, STF-31 (GLUT1 inhibitor). 121 It has been found that in the intestinal cells, coronavirus increases the glucose absorption through sodium ion-dependent glucose transporters known as SGLT1. 122 In DENV infected cells, it has been successfully demonstrated that treatment of infected cells with sodium oxamate and 2-deoxy-D-glucose (2DG) results in inhibition of glycolysis and thus, in DENV replication. 123, 124 Metabolically, ZIKV infection in human cells leads to increase in glycolysis. ZIKVinfected cells use increased glucose for the generation of TCA cycle intermediates. 125 Phloretin has been shown to be effective in ZIKV infected cells. 126 Moreover, inhibitor quercetin has been demonstrated to target GLUT1 in ZIKV, DENV-2, HCV, and Polio virus. 127 In COVID-19, lipogenesis (process of synthesis of fatty acids and triglycerides) is needed for virus packaging. 128, 129 Hence, any intervention in glycolytic pathway of host will downregulate lipogenesis leading to an inhibition in pyruvate production and will eventually prevent it from entering into TCA cycle. 129 Various glycolytic inhibitors that are designed against AMPK (AMP-activated protein kinase, the ultimate energy-sensor in eukaryotic cells which shut down ATP-consuming processes) are metformine, lipoic acid, resveratrol, ivermectin and so on. 121 Some common inhibitors targeting the host glycolytic pathway of +ssRNA viruses are listed in Table 3 . 

Host cell glycolytic pathway hijacked by viruses: The process starts with the intake of glucose into the cell, metabolism to G-6-P (glucose-6-phosphate) and then to pyruvate. Pyruvate is converted into lactate via glycolysis, which is then secreted out of the cell or Acetyl CoA (AcCoA) which is taken up by TCA cycle. Different viruses confiscating the glycolysis steps are shown in green.

Post-translational modifications of cellular proteins by attachment of ubiquitin or ubiquitin like modifiers leads to activation of innate and adaptive response. Protein ubiquitination is an enzymatic cascade involving covalent attachment of ubiquitin to target protein. 138 Ubiquitin is highly conserved protein composed of 76-amino acids, containing lysine residue at positions Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63. 48 Protein ubiquitination is a highly versatile and reversible event that controls the fate of the protein depending on the position of lysine in ubiquitin chain which is interacting with targeted protein. For instance, conjugation of ubiquitin at Lys48 classically designates the ubiquitinated protein as a target for proteasomal degradation, while Lys63 based ubiquitin chains primarily control protein trafficking among sub-cellular components and enzyme activity. 139, 140 Ubiquitin mediated protein degradation is not only playing a role in regulation of protein turn-over but also regulates DNA-damage repair, apoptosis, cell-cycle, cellular growth, and signal transduction. 141 Ubiquitination pathway comprises of three enzymes: ubiquitin-activating enzyme E1 responsible for forming an E1-ubiquitin thioester intermediate, ubiquitin-conjugating enzymes E2 responsible for transferring ubiquitin to targeted proteins, and ubiquitin ligases E3 usually involved in determining substrate specificity. 142 A reverse of the process of ubiquitination is deubiquitination, where ubiquitin residues are cleaved off from target protein by deubiquitinating enzymes (DUBs) or ubiquitin-specific proteases. 143 The ubiquitinated protein is recognized by 26S proteasome for degradation, and recycling of ubiquitin is carried out by DUBs. 139 Host-cells utilize UPS as a primary defense mechanism to counteract incoming pathogens such as viruses, by making them easily recognizable to T-cells. 142 As obligate intracellular pathogens, viruses have evolved strategies to antagonize host cell antiviral responses including molecular mimicry of key enzymes such as of ubiquitin, ubiquitin ligases, or action as DUBs to subvert the host cellular machinery for supporting their life cycle. Not only this, some viruses also use ubiquitin system to gain entry inside the host cell. 48 Therefore, a detailed understanding of virus-mediated suppression of host antiviral response by viral analogs infiltrating ubiquitin dependent pathways will deliver valuable information for antiviral drug discovery.

ZIKV envelope protein (E) is polyubiquitinated with the help of E3 ubiquitin ligase TRIM7 (Tripartite motif) that further drives entry, tropism, and pathogenesis of ZIKV. 144 Japanese Encephalitis virus (JEV), another example of +ssRNA virus, uses UPS for productive entry of virus into host cell by targeting a stage between virus internalization and initial translation of RNA genome after uncoating. A non-degradative ubiquitination step is utilized by DENV where ubiquitination of host protein TIM-1(receptor for DENV) at Lys338 and Lys346 is responsible for virus internalization and early entry step. 145 UBR-4, another E3-ubiquitin ligase of host cells, is specifically used by DENV non-structural (NS5) protein that inhibits Interferon-1 (IFN-I) signalling pathway after proteasomal degradation of the transcription factor STAT2, which is responsible for enhancing host IFN mediated antiviral response. 146 Some virus families such as coronaviruses, codes their own deubiquitinating enzymes such as PLpro that not only possess proteolytic activity but is also responsible for hijacking host antiviral response after deubiquitination of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and interferon regulatory factor 3 (IRF3) of host cell resulting in downregulation of host innate immune response. 147 SARS-CoV-2 PLpro preferentially cleaves ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from IRF3 resulting in attenuation of type I interferon responses, whereas SARS-CoV-PLpro predominantly targets cleavage of ubiquitin chains from targeted substrates. 148 Interestingly, nsP2 of CHIKV, SINV, and SFV ubiquitinates Rpb1 (a catalytic subunit of the RNA polymerase II complex) inducing its degradation, eventually hindering the activation of cellular genes and downregulating cellular antiviral response. 149 In addition to it, Lys48-ubiquitination of capsid protein of VEEV (Venezuelan Equine Encephalitis Virus) orchestrates the UPS for capsid degradation to allow the release of viral RNA into the cytoplasm for replication and translation to occur. 18 UPS plays a critical role in initial stages of replication for both MAYV and Una virus (UNAV) as explicated from proteasome inhibition studies. 150 Under these aspects, proteasome inhibitors have been reported as a therapeutic strategy to block UPS to inhibit replication of viruses as, coronaviruses 49 , astrovirus 48 , picornaviruses 151 , and rotaviruses. 152 Studies suggest that a proteasome inhibitor MG132 played an inhibitory role against murine coronavirus by promoting accumulation of viral RNA in endosomes, thereby inhibiting its release into the cytoplasm. 49 Treatment with MG132, lactacystin, bortezomib etc., are reported to cause a significant virus inhibition for VEEV, EEV, MAYV, UNAV, and CHIKV. 149, 150 The coronaviral protease PLpro is also an attractive antiviral drug targets because of its deubiquitinating activity that is essential for coronaviral replication. Targeting coronaviral PLpro will not only suppress the deubiquitinating and deISGylating activities, but will also help in upregulation of cytokines and chemokines essentially required for the activation of the host innate immune response against viral infection. Based on this approach, inhibitors such as GRL0617, rac5c, VIR250, VIR251, flavonoids, naphthalene based compounds etc. are reported previously to dysregulate activity of PLpro of SARS-CoV-2, SARS, and MERS. 153, 154, 155 Understanding the mechanisms by which the UPS is involved in the process of viral life cycle will provide deeper insights into the key virus-host interactions during early infection and may provide novel targets for further therapeutic development.

Polyamine are small, abundant, flexible, and positively charged molecules derived from ornithine and are involved in several cellular processes including proliferation, apoptosis, transcription, translation, DNA/RNA stabilization, and ion channel regulation in both mammalian and non-mammalian cells. In the metabolic pathway as summarized in Figure 3 , arginine is first changed to ornithine, which is further decarboxylated to putrescine via ornithine decarboxylase 1 (ODC 1) ( Figure 3 ). Putrescine is subsequently converted into spermidine and spermine with the help of their respective enzymes spermidine synthetase (SRM) and spermine synthetase (SMS) respectively ( Figure 3 ). Steady-state levels of polyamines are maintained either by regulation of ODC1 activity to control polyamine synthesis or by reducing polyamine pools with the help of catalytic enzymes like spermine acetyltransferase (SAT1), spermine oxidase (SMOX), and polyamine oxidase (PAOX). 51 Spermidine and spermine can be catabolized back to putrescine after addition of an acetyl group by SAT1 enzyme (Figure 3 ). Polyamine expression, synthesis, and degradation are highly regulated processes. For instance, ODC-1 activity is hindered by ODC-1 antizyme (OAZ1). Moreover OAZ1 translation is regulated by polyamine dependent translational frameshifting and also by antizyme inhibitor (AZIN1). 51 Furthermore, in eukaryotes spermidine acts as substrates for hypusination of a specific eukaryotic initiation factor 5A (eIF5A) with the help of two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), facilitating transcription, translation, and protein synthesis. 17 Viruses rely on polyamines for numerous stages of their life cycle including genome packing, replication, and translation of proteins. Therefore, a thorough understanding of how viruses utilize host cell polyamines for their cycle would pave new path way for discovery of novel strategies for combating viral infections.

NS5A and core proteins of HCV are reported to suppress level of ODC1 and SAT1 but elevates SMOX, which leads to diminished concentrations of spermine and spermidine, enhancing virus replication. Interestingly, polyamines are reported to facilitate binding and entry of coronavirus and flaviviruses. 17 It is also postulated in a study that the entry of DENV stimulates the overexpression of eIF5A, which prolongs survival of virus infected cell. 156 CHIKV has evolved with a unique strategy to prolong its survival against host antiviral response. CHIKV develops resistance to polyamine deletions through two mutations in the nsP1. These mutations ensued increase in viral replication in polyamine depleted cells. 17 Intriguingly, studies in SFV have shown that polyamines are not present on viral capsid, but is involved in promoting RNA synthesis. Conversely, polyamine depletion results in a marked decrease in activity of RNA polymerase in cells infected with SFV. 157 SAT1 is upregulated for CHIKV and ZIKV, in response to type I IFN stimulation, resulting in depletion of spermidine and spermine, ultimately restricting viral infection, since the depletion of polyamines limits the expression of nsPs, the viral polymerase and hence, the replication. 51 Reducing polyamine levels could, therefore, restrict the rate or even initiation of virus replication. Difluoromethornithine (DFMO), an inhibitor of ODC1 is documented to inhibit infections caused by CHIKV, ZIKV, MERS, SINV, JEV etc. by depleting levels of polyamine. 51 An offshoot of the polyamine metabolism is the cellular hypusination pathway, in which spermidine acts as a substrate molecule for enzyme DHPS to generate unique amino acid hypusine in eIF5A for activating it. 158 Hypusinated eIF5A facilitate mRNA nucleocytoplasmic transport and mRNA stability. 158 Therefore, ciclopirox (CPX), deferiprone (DEF), and GC7 inhibitors targeting DHPS/DOHH averting hypusination of eIF5A, have proven to be a great approach to impede MHV and HCV. 159 A concise list of polyamine inhibitors and their target is provided in Table 4 . 

Targeting the stress granules is a novel therapeutic strategy to treat viral diseases. Stress granules (SG) are stalled mRNA and protein assemblies that get accumulated during translation initiation in response to stress. SGs are formed in response to various biological functions such as inflammation, apoptosis, many signalling pathways and so on. 161 SGs play an important role in pathogenesis of viral infections, neurodegenerative diseases, aging, etc. Therefore, targeting the stress granules has become a potential therapeutic strategy to treat human diseases. In mammalian eukaryotic cells, most of the mRNA undergoes transcription inside the nucleus and after that, transported into the cytoplasm where it undergoes translation and expression. The mature mRNA is not translated into the proteins immediately in case of cell stimulation or disturbance. Hence, these temporarily-stalled mRNA complexes polymerize with RBPs (RNAbinding proteins) to form mRNP granules (messenger ribonucleoprotein) known as SG, Cajal bodies, P-bodies (processing bodies), or germ granules. SG are dynamic granules formed in the cytoplasm and their formation is stimulated by oxidative stress, viral infection, heat shock, hypoxia, etc. Stress granule formation mechanism is a type of adaptive regulatory process that protects the cells from apoptosis during adverse conditions. Virus invasion pose adverse stress conditions to the host. The viral interference with the host genome and antiviral responses to the same, drive SG formation in order to govern viral RNA replication and translation. These virus-induced SGs are called anti-viral SGs. Some cellular proteins like G3BP, T cell intracellular antigen-1 (TIA-1), and TIA-1-related protein (TIAR) were observed to be primarily involved in assembly of SG. 162 In coronaviruses, the significance of SG in viral infections is still not so clear. In SARS-CoV-2, it has been found that the nucleocapsid protein (N protein) is formed at high levels in infected cells and recruit the SG protein G3BP1 (GTPase-activating protein (SH3 domain)-binding protein), highlighting its potential role in SG inhibition. 163 Recent proteomic studies have also highlighted that N-protein of SARS-CoV-2 associates with host SG nucleating proteins G3BP1 and G3BP2, attenuating the formation of SG and enhancing virus replication and packaging into new virions. 163, 164 A previous study for WNV and DENV has emphasized the role of NS3 protein which interacted with TIA-1 or TIAR host proteins and resulted in down-regulation of SG formation in virus infected cells. 165 Furthermore, ZIKV proteins NS3 and NS4A are interrelated to translational repression whereas the capsid proteins NS3/NS2B-3 and NS4A were reported to inhibit the SG assembly. ZIKV RNA displays interactions with G3BP1 whereas the viral capsid proteins interacts with host G3BP1 and Caprin-1 proteins, suppressing the SG mediated antiviral response of the host cell. 166 Many other viruses induce the formation of SG such as CHIKV, SFV, SINV, picornavirus, SARS-CoV-2, poliovirus etc. by diverse modes of regulation of SGs. Stress response produced by the SGs is antiviral in nature and to counteract this antiviral response, many viruses like CHIKV have manipulated the host machinery for their own benefit. Such viruses block SG response by sequestering G3BP. 167 This sequestration occurs with the help of two conserved motifs namely FGDF motifs that are present in C-terminal of nsP3 in the viruses such as CHIKV, SFV, etc. 168 This viral nsP3 protein functions by disrupting the SGs and nsP3 facilitates this disruption process by recruiting this host G3BP protein via FGDF motifs. 169 Thus, targeting such host proteins like G3BP can actually induce the stress response which, in turn, can induce antiviral activity against such viruses. Studies regarding targeting the host protein G3BP are still carried out to initiate antiviral activity against viruses that facilitate stress granule mediated response.

Another promising broad-spectrum antiviral drug target is the cellular protein homeostasis pathway maintained by an array of molecular chaperones that control a number of processes such as protein translation, correct folding, degradation, apoptosis, cell cycle regulation, and intracellular trafficking. 170, 171 Chaperones such as heat shock proteins (Hsp70 and Hsp90), are reported to play key roles in life cycle of many +ssRNA viruses such as DENV, HCV, ZIKV, CHIKV, YFV, WNV etc. Many viruses depends upon the chaperones to fold and assemble viral proteins. Hsp70 directly interacts with RdRp domain of JEV NS5 protein, stabilizes the RTC and positively regulates the genomic replication. 172 ZIKV requires Hsp70 to facilitate virus entry into host cell, formation of RTC, and egress from host cell. 173 Detailed role of recruitment of Hsp70 in entry and capsid maturation of flaviviruses is still not clear and is presumed to be linked with capsid uncoating and reduction in its stability. 174 Hsp70 isoforms are required for entry, replication, and virion biogenesis of DENV. 171 Chaperone proteins of Hsp70 participates in NS3/4A cleavage and replication of YFV. 175 In addition to these, Hsp70 interacts with NS5A protein of HCV that is essential for replication and virion assembly. 176 nsP3 and nsP4 proteins of CHIKV interacts with Hsp that promotes virus replication. 65 Quercitin, an inhibitor of Hsp, is reported to attenuate replication of HCV. 177 Geldanamycin and SNX-2112, inhibitors of Hsp, showed dramatic reduction in CHIKV viral titers and also abridged inflammation in a CHIKV mouse model of severe infection and musculopathy. 65 HS-72 inhibits entry of DENV by disrupting interaction of Hsp70 with DENV receptor complex. 178 However, the interplay between viruses and chaperones is still not characterized in depth and their roles in life cycle of many viruses are still unclear.

Among the repertoire of host mechanism that viruses use for regulating their gene expression, noncanonical translation such as −1 programmed ribosomal frameshifting (−1 PRF) is another strategy used by viruses to increase coding capacity of their constrained genomes. 179, 180, 181 PRF is a translation recoding mechanism wherein the mRNA signal (frameshift signal) induces the translating ribosomes to slip back 1 nucleotide in 5' direction (-1 PRF) or in the 3' direction (+1 PRF), so that the translation continues in a new reading frame by utilizing alternative start sites and bypassing termination codons. 21, 181 This enables viruses to encode multiple proteins from a single mRNA and may confer selective advantage to viruses. 182 Typically a frameshift signal is comprised of three parts: a heptameric slippery site where frameshifting can occur while maintaining non wobble base pairing between tRNA and mRNA, a short spacer sequence between the slippery site and downstream secondary structural element, and a strong mRNA secondary structural element such as a pseudoknot to facilitate -1 PRF by transiently stopping the incoming ribosome and eventually letting the tRNAs to realign within the slippery sequence. 183, 184 Sequence of this -1 PRF is conserved as it has to maintain structure while coding for overlapping regions, thus eliminating the possibility of development of mutations to become drug resistant and making it an attractive target for discovery of new antivirals. 185 Alphaviruses are made up of two ORFs that encodes polyproteins that undergo proteolytic cleavage to produce structural and nsPs. Two recoding signals have been reported for alphaviruses: termination codon region (TCR) located at opal (UGA) termination codon at the boundary between nsP3 and nsP4 genes, and the -1 PRF signal located near the 3' end of 6K gene which leads to the production of trans-frame product that functions as an ion channel and is known to be important for neuropathogenesis in SINV. 181, 186, 187 NS1' protein of flaviviruses (JEV and WNV), a larger-NS1 related protein involved in viral replication and regulation of innate immune response, is also a product of -1 PRF event that occurs near the start point of NS2A gene and is playing a role in viral neuroinvasiveness. 188 ORF1a and ORF1b of coronaviruses including SARS-CoV-2 are slightly overlapping, and since ORF1b lacks translation initiation site, proteins encoded by ORF1b are translated by -1 PRF mechanism leading to the production of fusion polypeptide proteolytically cleaved by viral proteases. The first protein produced after -1 PRF is the RdRp which is a key replicase protein of coronavirus required for genomic replication thus, highlighting the imperative role of -1 PRF in coronavirus infection cycle. 185, 189 Studies revealed that -1 PRF machinery can be impeded or altered by small molecules interfering SARS-CoV-2 and SARS-CoV replication machinery, such as antisense peptide nucleic acids 185 , 2-methylthiazol-4-ylmethyl)-[1,4]diazepane-1carbonyl]amino}benzoic acid ethyl ester (MDTB) 190 , merafloxacin, and ivermectin. 184 A host RNA binding protein, annexin A2 slows down the frameshifting efficiency after binding to pseudoknot of Infectious bronchitis virus (IBV). Host interferon stimulated protein shiftless, is a broad-spectrum suppressor of -1 PRF pathway in HIV, SARS-CoV-2, and SINV. 21, 191 

Viruses dwell on host nucleosides for their genome replication. During infection, viruses discharge their cargo into the host and utilizes host cell's machinery to replicate their own genome, thus, producing progeny viral particles. Host proteins that are associated with synthesis of nucleosides can therefore be targeted as antiviral therapeutics. The inosine monophosphate dehydrogenase (IMPDH) is an essential enzyme which catalyses de novo synthesis of guanine nucleotides. Guanine biosynthesis can be inhibited by using a broadspectrum antiviral called ribavirin. Ribavirin in combination with PEGylated interferon-a, has been used as a standard treatment for chronic HCV. 192 An immunosuppressant known as mycophenolic acid has also been shown to reduce CHIKV replication by depleting intracellular GTP pool. 164 Hence, nucleotide pool depletion (GTP more specifically), has emerged as a promising strategy for suppressing viruses particularly flaviviruses. Dihydroorotate dehydrogenase (DHODH) is an important enzyme of the de novo pyrimidine biosynthesis pathway. It can be inhibited using brequinar, an immune-suppressant and anti-metabolite in cancer. 193 It has been demonstrated to inhibit DENV serotypes 1, 2, and 3. A compound NITD-982 analogue has been shown to inhibit host DHODH but the compound didn't show efficacy in in vivo studies because of exogenous supply of pyrimidines in the diet. In addition, a uridine analog and other intracellular nucleotide-depleting compound called 6-azauridine functions as a competitive inhibitor of OMP (orotidine monophosphate decarboxylase enzyme) which results in the depletion of UTP pools. 194 Consequently, 6-azauridine has been shown to inhibit replication of some viruses like CHIKV and SFV. 195 Inhibition of de novo pyrimidine synthesis also occurs through an antiparasitic drug called atovaquone and has been shown to inhibit replication in CHIKV via dose dependent manner. 106 

Glycosylation is one of the many post translation modifications which is ubiquitous and contributes in multitude of important biological roles. During replication, viruses exploit this host glycosylation machinery for the production of their own glycosylated proteins in the secretory pathway. 196 Viral replication especially for +ssRNA viruses such as, SARS-CoV-2 19 , ZIKV 197 , DENV 198 , and flaviviruses 199 occurs mostly in ER derived membranous structures that are induced by the nsPs of these RNA viruses. Viruses manipulate and exploit the functions of ER to promote their life cycle involving entry, translation, viral replication, morphogenesis, and egress. 200 Like other viruses, SARS-CoV-2 also follow this life cycle to promote its exponential growth which, in turn, offers opportunities to look for essential host proteins and pathways for SARS-CoV-2 that could act as hotspots to be targeted with therapeutic objectives. 201 The initial step of N-linked glycosylation starts from the membrane of ER on which precursor tetradecasaccharide gets assembled. In ER lumen, this precursor is attached via a covalent en bloc attachment of the asparagine residue to the nascent polypeptide. 202 From this point, these precursors are processed by series of processing enzymes that trim down and remould core oligosaccharide in ER and golgi apparatus resulting in the formation of diverse classes of glycans (oligomannose, hybrid as well as complex-type-glycans). 196 In context of viruses, it is evident that some virus particles (such as HCV) bypass golgi apparatus glycan maturation, therefore, bud off early and translocate in the glycosylation pathway from ER to plasma membrane or do not follow the secretion pathway because of some unusual glycans present on viral glycoproteins. 203 Depending on the type of virus, host glycans serve as primary receptors, co-receptors or attachment factors. 204 It has been observed that epitope masking occurs by glycosylation on coronavirus spike proteins. It appears that coronaviruses occlude receptor binding domains by using N-linked glycans. 201 In SARS-CoV-2, the genome encodes nsPs and accessory proteins which are responsible for virus assembly, virulence, and recruits components of host's secretory pathway. However, the coordination of assembly of viral structural proteins is still unclear. ZIKV has been reported to interact depending on major ER proteins such as SPC proteins (ER-associated signal peptidase complex), EMC (ER membrane complex), and ER translocon. 197 Apart from this, EMC proteins associate with ER translocon Sec61, and OST (oligosaccharyltransferase) complex proteins which promote ZIKV infection. 197

Understanding of ER glycosylation pathway gives an insight towards the active involvement of endoplasmic reticulum in viral infection, thus, bound to have therapeutic implications. Intriguingly another novel strategy to design inhibitors relies on ER-associated components, understanding glycans, their modes of function and viral glycobiology. In SARS-CoV-2 iminosugars have shown broad-spectrum antiviral activity in vivo and in vitro. 199 However, iminosugars are still to be approved for the treatment of viral infections and their potential use as host-targeted antiviral therapies is still to be investigated. Figure 4 provides a simplified presentation of N-Linked glycosylation pathway and Table 5 comprises a list of antivirals acting against glycosylation pathways.

Simplified presentation of N-Linked glycosylation. The oligosaccharide core consists of two N-acetylglucosamine (GlcNAc, blue), nine mannose sugars (Man, red), and three glucose (Glc, green). Nascent polypeptide enters ER through Sec61 in which precursor core oligosaccharide gets transferred onto asparagine residues (I). Then the trimming of two terminal glucose moieties on the core oligosaccharide occurs in the presence of Glucosidase I (GI) (II) and GII (III), which leads to the folding of protein into native structure with the help of chaperones. The last trimming of glucose moiety occurs by GII and the glycoprotein finally attains a native conformation (IV). The glycoproteins that attain a native conformation pass gets their mannose residues removed (V) and pass through the canonical secretory pathway (VI). Eventually, misfolded glycoproteins are rapidly recycled through autophagy after demannosylated (VII). Viruses hijack EDEMosomes and form double membrane vesicles that act as a platform for viral replication. 

defense: 2.10.1. Cytokine signalling cascade and immune regulation:

The first line of defence against any viral infection comprises of pattern recognition receptors (PRR) such as RIG-I-like receptors (RLRs) and Toll-like receptors (TLRs) that are primarily accountable for detection of viral RNA genome and its intermediates ( Figure 5) . Upon virus infection, the single-stranded or double-stranded viral RNA leads to activation of TLR/RIG-I/MDA-5, which transduces viral signal through adapter proteins MAVS (Mitochondrial activator of virus signalling) and MyD88, ultimately leading to initiation of downstream signalling cascades ( Figure 5 ). 113 After virus recognition, a series of kinases belonging to IκB kinase (IKK) complexes including IKKα, IKKβ, IKKγ or TANK-binding kinase 1 (TBK1), and IKKε are activated subsequently leading to phosphorylation of transcription factors such as IRF3 and NF-κB. 206 Phosphorylation of these transcription factors consequently leads to their translocation to the nucleus cooperatively inducing formation and release of proinflammatory cytokines (G-CSF , IL-1β, IL-2, IL-8, IL-10, IL-17, TNFα, MCP-1, GMCSF, and CCL3), and antiviral type I IFNs (IFN-α and IFN-β) ( Figure 5 ). 8 inflammatory cytokines mediates direct antiviral effects that subverts viral replication after binding to receptors present on infected cells or neighbouring cells and eventually activation of tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1). 10 Signal transducer and activator of transcription 1 and 2 (STAT 1 and STAT 2), the major substrates of JAK1 and TYK2, after phosphorylation stimulates expression of ISG (Interferon stimulated genes) after migration to nucleus ( Figure 5 ). While STAT1 is essentially required for IFN-λ and IFN-γ signalling, STAT 2 is crucial for IFNα and IFN-λ signalling. 207 Control of STAT signalling includes posttranslation modifications such as methylation 208 , acetylation 209 , and ISGylation 210 that plays a role in promoting signalling whereas dephosphorylation and sumoylation pathways 211 are reported to inhibit it. Cytokines released by virus infected cells then plays a role in modulation of adaptive immune response by activating immune cells such as macrophages, B lymphocytes, and T lymphocytes that aids in elimination of virus.

The type I IFN system present in vertebrates epitomizes an important mechanism to block the intra-host growth of viruses across wide-ranging taxonomic classes. Conversely, viruses have co-evolved with humans and have developed multiple strategies to evade immune recognition and to suppress antiviral responses orchestrated by IFN. ORF 6 protein of SARS-CoV-2 inhibits IFN-β production by interacting with nuclear importing factor karyopherins blocking IRF3 nuclear translocation. 212 SARS-CoV-2 is also highlighted to antagonize IFN signalling by using three approaches: i) ORF3a, ORF7b, M, ORF7b, nsP1, nsP6, and nsP13, proteins that are reported to suppress STAT1 phosphorylation; ii) ORF7a, nsP6, and nsP13 are reported to inhibit STAT2 phosphorylation; iii) and ORF-6 impedes STAT1 nuclear translocation. 212, 213 SARS-COV-2 also provokes a fatal immune reaction after abnormal and uncontrolled production of pro-inflammatory cytokines, commonly termed as "cytokine storm". 20, 86, 129, 213, 214, 215 SARS-CoV-2 activates T lymphocytes to produce GMCSF and IL6 which further leads to downstream activation of CD14 + /CD16 + monocytes to produce bulk quantities of IL6, TNFα, IL-8, IL-10, CCL2, CCL3, and other cytokines, followed by infiltration of neutrophils and macrophages in lung tissue resulting in systematic inflammatory response and acute respiratory distress syndrome (ARDS). 20, 214, 215, 216 To avoid its recognition, SARS-CoV or MERS-CoV virus shields itself or its intermediates (dsRNA or ssRNA) within DMVs preventing its exposure to PRRs. To disguise host cell machinery, SARS-CoV is also reported to inhibit IRF3 by preventing its hyperphosphorylation, dimerization or its interaction with cofactor CREB-binding protein (CBP). 217 Not only this, SARS-CoV is also reported to inhibit nuclear import of transcription factor. 218 Interestingly it has also been reported that ORF3b, ORF 6, and N protein of SARS-CoV inhibits expression of IRF3 which further impedes expression of IFN-β. 219 In a similar context, PLpro of SARS-CoV and HCoV-NL63 are reported to interact with IRF3 preventing its activation. ORF9b protein of SARS-CoV is also responsible for proteasomal degradation of MAVS. Moreover ORF4a, ORF4b, ORF5, and M protein of MERS-CoV are identified to prevent IRF3 translocation. SARS-CoV ORF3b, ORF9b, ORF6, nsP1, nsP7, and nsP15 proteins are observed to disturb IFN induction, and most importantly anti-IFN function of nsP1 protein is based on its differential ability to degrade host mRNA to block host mRNA translation, sparing its own viral mRNA. 218 Several protein of MERS and SARS are documented to inhibit IFN signalling, for example ORF6 protein of SARS is documented to deter nuclear import of STAT1 by sequestering nuclear import factor karyopherin alpha 2 to intracellular membranes. 218 CHIKV encoded proteins nsP2, E2, and E1 proteins are documented to inhibit MDA5/RIG-1 dependent activation of IFN-β promoter whereas MAVS-Mediated Induction of the IFN-β promoter is strongly impeded by nsP1, nsP2, E2, and E1 proteins. In addition to these, nsP4 and capsid protein of CHIKV is capable of antagonizing TBK1-medated induction of the IFN-β promoter and IKKε-Mediated Induction of the IFN-β Promoter is downregulated by nsP2, E2, and E1 proteins. nsP2 of CHIKV is also stated to strongly antagonize IRF3/IRF-5D mediated induction of the IFN-β promoter. 220 SINV and VEEV are described to disrupt IFNα/β signalling by inhibiting accumulation of tyrosine phosphorylated STAT1 and STAT2. 221 Flaviviruses have also evolved many counter-strike mechanisms to antagonize host's IFN response during infection by directly antagonizing activation of specific PRR or by inhibition of downstream signalling molecules of IFN pathway. A phosphomimetic motif within NS3 protein of DENV and WNV is reported to bind RIG-1 ultimately blocking its translocation to mitochondria. 222 Recent studies have uncovered that NS4A of DENV binds and sequesters MAVS, eventually hindering its interaction with RIG-1 and inhibiting downstream innate immune signalling cascade. 223 ZIKV NS4a interferes with RLR signalling by interrupting RLR-MAVS interaction, preventing induction and secretion of IFN and proinflammatory cytokines. 224 Recent work suggested that ZIKV is able to evade RIG-1 and MDA-mediated immunity by disrupting interactions with cellular scaffold proteins 14-3-3η and 14-3-3ε, where 14-3-3ε is responsible for cytosol-to-mitochondrial translocation of RIG-I and 14-3-3η expedites MDA5 translocation to mitochondria, thereby endorsing antiviral IFN induction. 225 Similar to DENV NS3, ZIKV NS3 binds to 14-3-3ε and prevents cytosol to mitochondrial translocation of RIG-1. 222 WNV induces expression of suppressors of cytokine signalling 1 and 3 (SOCS) after interacting and activation of TAM (Tyro3/Axl/Mer) receptors on dendritic cells, finally affecting JAK1 pathway and its downstream signalling. Many viruses antagonize STAT1 and STAT2 signalling functions with the help of their nsPs. NS4b of DENV is documented to reduce STAT1 phosphorylation and ISRE-dependent gene expression, in response to IFN-β. 226 Additionally, NS5 protein of DENV was shown to bind to human STAT2, which reportedly blocks its phosphorylation thereby, its ability to transcriptionally upregulate ISGs. NS5 protein of Yellow fever virus (YFV) interacted with STAT2-allowing downstream inhibition of ISRE activation. 227 A summarized list of host factors exploited by +ssRNA viruses to evade inflammatory antiviral response is provided in Table 6 . Additionally, Table 7 provides a comprehensive list of antivirals targeting the host cytokine signalling pathway.

It has also been observed that many +ssRNA viruses including DENV, CHIKV, SINV, WNV, JEV, Ross river virus, YFV etc. displays antibody dependent enhancement (ADE) of macrophages and monocytes to increase their overall replication. 228, 229 ADE occurs when preexisting antibodies (from first viral infection) in a body, binds to same virus (of different serotype) during second infection and this antibody-virus complex binds to circulating monocytes. 230 In contrast to normal antigen-antibody reaction, these antibodies will not neutralize virus but will result in an overall exacerbation in viral replication with the development of more severe disease. Paradoxically, ADE facilitates the upregulation of SOCS3 inhibits the JAK/STAT signalling pathway with an overall increase in expression of IL6 and IL10, enabling the virus to take full advantage of immune suppressive and anti-inflammatory environment generated by production of IL10, ultimately inhibiting the IFN α/β signalling cascade. 228, 229, 231 A more comprehensive knowledge of important virus-host interactions of ADE pathway is required to identify cell-targeting drugs against effectors of ADE, which can be used as a prophylactic treatment in severe cases. ZIKV, SARS-CoV-2

Enhances IFN-α signalling, activates the IFN-α-JAK/STAT signalling pathway leading to alleviated expression of MxA, an antiviral protein 244

Could inhibit the NF-κB pathway 244 DENV

Stimulation of IL-12 secretion and conversely inhibition of IL-6 production, CHIKV, SARS-CoV, HCV thereby enhancing the production of IFNγ 244

In the recent times, monoclonal antibodies (mAbs) are being directed against the host factors instead of directing against viral proteins. Antiviral mAbs are immunoglobulins with a single isotope and defined specificity. These antibodies exhibit therapeutic effects with the help of antigen-binding fragment (Fab) and can be used against particular disease targets such as HCMV. 245 mAb therapy is just like passive immunotherapy which targets direct and rapid viral agent instead of developing a long-term immune response against that viral pathogen. In contrary, vaccine stimulates the host's endogenous cellular and humoral immune responses to deliver sustained defensive immunity. There has been accumulating evidences to show that antiviral mAbs can interact both directly and indirectly with different constituents of immune system. 246 It depends upon the type of virus, viral antigen that is being recognized and the antibody itself. Direct interaction includes ADCVI (antibody dependent, cell-mediated virus inhibition) while indirect methods include engagement of the immune response of the host, etc. Thus, antiviral mAbs treatment can also trigger endogenous immune response of the host. Few examples of mAbs designed and targeted against host proteins are shown in Table 8 . 

The widespread predominance of viral infections such as CHIKV, DENV, ZIKA, HCV, JEV SARS etc., and the re-emergence of viral infections in the form of outbreaks such as the ongoing pandemic caused by SARS-CoV-2 have led to an immediate demand for development of new therapeutic approaches to combat these deadly infections. Viruses, not only depend upon molecular machinery of the host cell for their replication, but also transcribes and translate their own proteins for enhancing their spread and infection. In order to counteract host antiviral response generated after virus entry, specialized viral enzymes hijacks and manipulates critical cellular enzymes and signalling proteins. Presently, diverse antiviral drugs targeting the viral proteins are either clinically approved or are in later stages of trial. Conventionally, most of these drugs functions by targeting viral proteins (polymerases and proteases) and this traditional therapeutic approach has also proven to be highly beneficial in combating several viral infections. However, rapid regeneration of drug-resistant viruses have been reported with the usage of antivirals drugs based on this strategy that has eventually resulted in failure of this novel approach for some chronic viral infections. Therefore based on the fact of development of antiviral resistance, and global spread of viral infections, a deeper understanding of mechanisms behind immune dysregulation and alternative antiviral approaches are necessarily required for clinical management of severe viral infections. The present review focuses on comprehensive understanding of host antiviral responses, immune responses and the advances made in the development of host-targeted drugs, primarily for +ssRNA viruses. The article also summarizes the key host-cellular factors or mechanism hijacked by viruses for their replication, including detailed information of hostbased antiviral therapeutics already available for upregulation of immune response of the host. Since the genetic variability of host is quite less in comparison to viruses, host-based antiviral drugs are less likely to become ineffective against virus or its variants. In concordance to it, a combination of virus-targeted and host-targeted antiviral drug combination can also be tested for synergistic effects, if any. Besides virus-targeting antiviral drugs acting against viral specific proteins, host-based antiviral drugs will have the potential to be broad-spectrum as well. High-throughput molecular profiling techniques and computational biology are providing new hopes to treat the deadly viral infections and focusses on the importance of host in viral pathogenesis providing unparalleled opportunities for diagnostics, better therapeutics and vaccines.

A major pitfall of host-targeted antiviral drugs is related to cellular side effects and cytotoxicity as they targets the cellular pathways of host cell essential for host survival. 253, 254 Alisporivir, an inhibitor of cyclophilin A, displayed mild to moderate hyperbilirubinemia and hypertriglyceridemia, in phase II of its clinical trials. 253, 255, 256 Not only this, for host-directed therapeutic approaches, there is a possibility that viruses may use an alternate host factor or can modify the affinity towards the existing host dependency factor. Pertinently, host-targeted drugs are also subjected to genetic polymorphisms of host that may alter their ability to block their target function. 256 For instance, 10-15% of patients displayed suboptimal response against HCV on treatment with alisporivir. 59 Another possible risk associated with use of host-targeted antivirals is poor translation of in vitro results to in vivo therapies. Drugs displaying excellent activities in cell-culture based assays might behave differently when studied in vivo because host systemic mechanisms may compensate the effect of blocked target. 257 For instance, VX-497, an inhibitor of IMPDH, potently inhibited HCV replication when tested in vitro but displayed poor activity when it was tested in patients. 100 A possible explanation for this could be the variations in the level and supply of nucleotides in in vitro and in vivo conditions that would have resulted in poor efficacy of inhibitors targeting the IMPDH pathway. Similarly, statins displayed good antiviral activity against HCV in vitro but poor efficacy was observed when tested in clinical trials, probably because the cellular level of cholesterol is different in vitro and in human subjects. 258 Moreover, host pathways involves a complex signalling cascade activating multiple pathways to generate a strong antiviral response. Therefore, identification of the host target and tracing the mechanism of action of identified drug is another challenge of host-targeted therapy. 253 Hence, quick and detailed understanding of positive impacts and side effects of hostbased antiviral drugs is necessarily required for development of an effective antiviral therapy against chronic viral infections. A better understanding of innate/adaptive responses of host cell, steps of viral life cycle, signalling cascades and host factors confiscated by viruses is a prerequisite to provide molecular insights for development of broad-spectrum antiviral therapy against recurring viral infections.

Structure and Classification of Viruses

Viral Pandemics of the Last Four Decades: Pathophysiology, Health Impacts and Perspectives

Chikungunya virus inhibition by peptidomimetic inhibitors targeting virus-specific cysteine protease

Japanese Encephalitis Outbreak

The History of Dengue Outbreaks in the Americas

Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS

Unraveling the host's immune response to infection: Seeing is believing

Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

Host Immune Response and Novel Diagnostic Approach to NTM Infections

Regulation of type I interferon signaling in immunity and inflammation: A comprehensive review

Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection

Inhibition of Chikungunya virus by an adenosine analog targeting the SAM-dependent nsP1 methyltransferase

Conformer and pharmacophore based identification of peptidomimetic inhibitors of chikungunya virus nsP2 protease

Structure and Function of Alphavirus Proteases

Specific Roles for Lipids in Virus Fusion and Exit Examples from the Alphaviruses BT -Fusion of Biological Membranes and Related Problems

The compound packaged in virions is the key to trigger host glycolysis machinery for virus life cycle in the cytoplasm. iScience

Targeting Polyamine Metabolism for Control of Human Viral Diseases

The Ubiquitin Proteasome System Plays a Role in Venezuelan Equine Encephalitis Virus Infection

Inhibition of SARS-CoV-2 viral entry upon blocking N-and O-glycan elaboration

Cytokine storm intervention in the early stages of COVID-19 pneumonia

Programmed −1 ribosomal frameshifting from the perspective of the conformational dynamics of mRNA and ribosomes

Host-directed therapies for bacterial and viral infections

Host-Directed Antiviral Therapy

Host-Directed FDA-Approved Drugs with Antiviral Activity against SARS-CoV-2 Identified by Hierarchical In Silico

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

Glycan-dependent chikungunya viral infection divulged by antiviral activity of NAG specific chi-like lectin

Coronavirus biology and replication: implications for SARS-CoV-2

In silico guided drug repurposing to combat SARS-CoV-2 by Targeting Mpro, the key virus specific protease

Inhibition of Chikungunya virus by an adenosine analog targeting the SAM-dependent nsP1 methyltransferase

Astrovirus Res Essent Ideas, Everyday Impacts, Futur Dir

Organization of the Flavivirus RNA replicase complex

Pathogenesis of Flavivirus Infections: Using and Abusing the Host Cell

Towards antivirals against chikungunya virus

Chikungunya virus infections: time to act, time to treat

RNA interference for antiviral therapy

Antiviral therapy: current concepts and practices

Transcriptome sequencing, microarray, and proteomic analyses reveal cellular and metabolic impact of hepatitis C virus infection in vitro

Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification

RNA-based mechanisms regulating host-virus interactions

Functional Genomic Strategies for Elucidating Human-Virus Interactions: Will CRISPR Knockout RNAi and Haploid Cells?

Interactions between Viral Nonstructural Proteins and Host Protein hVAP-33 Mediate the Formation of Hepatitis C Virus RNA Replication Complex on Lipid Raft

Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection

The human antibody response to influenza A virus infection and vaccination

Metabolic changes during respiratory syncytial virus infection of epithelial cells

Metabolic host response and therapeutic approaches to influenza infection

The Role of Lipid Metabolism in Influenza A Virus Infection

The Role of the Host Ubiquitin System in Promoting Replication of Emergent Viruses

The ubiquitin-proteasome system facilitates the transfer of murine coronavirus from endosome to cytoplasm during virus entry

An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction

Chikungunya Virus Overcomes Polyamine Depletion by Mutation of nsP1 and the Opal Stop Codon To Confer Enhanced Replication and Fitness

Host cell glutamine metabolism as a potential antiviral target

AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus

A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection

Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses

Suramin inhibits Zika virus replication by interfering with virus attachment and release of infectious particles

Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor

Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 phase 2b study

Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Curcumin Protects Neuronal Cells from Japanese Encephalitis Virus-Mediated Cell Death and also Inhibits Infective Viral Particle Formation by Dysregulation of Ubiquitin-Proteasome System

CuraChik : A Trial of the Efficacy and Safety of Chloroquine as Therapeutic Treatment of Chikungunya Disease -Full Text View -ClinicalTrials

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Chikungunya virus nsP3 & nsP4 interacts with HSP-90 to promote virus replication: HSP-90 inhibitors reduce CHIKV infection and inflammation in vivo

A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs

Ivermectin in Adults With Severe COVID-19. -Full Text View -ClinicalTrials

Lack of selective resistance of influenza A virus in presence of host-targeted antiviral

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): A phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial

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Seeking Membranes: Positive-Strand RNA Virus Replication Complexes

Envelope Lipid-packing as a Critical Factor for the Biological Activity and Stability of Alphavirus Particles Isolated from Mammalian and Mosquito Cells *

Lipid droplets and their component triglycerides and steryl esters regulate autophagosome biogenesis

Sphingolipids in mammalian cell signalling

Cholesterol effectively blocks entry of flavivirus

Fatty acid synthase and stearoyl-CoA desaturase-1 are conserved druggable cofactors of Old World Alphavirus genome replication

Reciprocal regulation of inflammation and lipid metabolism by liver X receptors

+)RNA viruses rewire cellular pathways to build replication organelles

Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis

Contemporary Strategies and Current Trends in Designing Antiviral Drugs against Dengue Fever via Targeting Host-Based Approaches. Microorganisms

Flavivirus control of lipid metabolism: implications for virion formation, function and pathogenesis

Critical role of lipid rafts in virus entry and activation of phosphoinositide 3′ kinase/Akt signaling during early stages of Japanese encephalitis virus infection in neural stem/progenitor cells

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

SARS-CoV-2 genomic and subgenomic RNAs in diagnostic samples are not an indicator of active replication

Switching Host Metabolism as an Approach to Dampen SARS-CoV-2 Infection

Membrane heist: Coronavirus host membrane remodeling during replication

The quest for host targets to combat dengue virus infections

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

Antiviral therapeutics for chikungunya virus

Requirement of cholesterol in the viral envelope for dengue virus infection

Imipramine Inhibits Chikungunya Virus Replication in Human Skin Fibroblasts through Interference with

Inhibition of Chikungunya Virus Replication in Primary Human Fibroblasts by Liver X Receptor Agonist

C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase*

The anti-dengue virus properties of statins may be associated with alterations in the cellular antiviral profile expression

U18666A, an intra-cellular cholesterol transport inhibitor, inhibits dengue virus entry and replication

Indirect Acting Antivirals ; Tricking the Virus through a Pristine Approach

Cholesterol Manipulation by West Nile Virus Perturbs the Cellular Immune Response

Armand-Frappier Outstanding Student Award -The emerging role of 25-hydroxycholesterol in innate immunity

An Open Pilot Study Exploring the Efficacy of Fluvastatin, Pegylated Interferon and Ribavirin in Patients with Hepatitis C Virus Genotype 1b in High Viral Loads

UJEMI PEARLS Use of Combinational Broad-Spectrum Antiviral Cocktail for Treating Current and Emerging Coronavirus Infections

Lipid Metabolism as a Source of Druggable Targets for Antiviral Discovery against Zika and Other Flaviviruses

Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus

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☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: