key: cord-0753148-ypkiptvh authors: Omolo, Calvin A.; Soni, Nikki; Fasiku, Victoria Oluwaseun; Mackraj, Irene; Govender, Thirumala title: Update on therapeutic approaches and emerging therapies for SARS-CoV-2 virus date: 2020-07-04 journal: Eur J Pharmacol DOI: 10.1016/j.ejphar.2020.173348 sha: 8d2496e8e40f0ee12a6c81076441ab3d30dd929c doc_id: 753148 cord_uid: ypkiptvh The global pandemic of coronavirus disease 2019 (COVID-19), caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in over 7,273,958 cases with almost over 413,372 deaths worldwide as per the WHO situational report 143 on COVID-19. There are no known treatment regimens with proven efficacy and vaccines thus far, posing an unprecedented challenge to identify effective drugs and vaccines for prevention and treatment. The urgency for its prevention and cure has resulted in an increased number of proposed treatment options. The high rate and volume of emerging clinical trials on therapies for COVID-19 need to be compared and evaluated to provide scientific evidence for effective medical options. Other emerging non-conventional drug discovery techniques such as bioinformatics and cheminformatics, structure-based drug design, network-based methods for prediction of drug-target interactions, artificial intelligence (AI) and machine learning (ML) and phage technique could provide alternative routes to discovering potent Anti-SARS-CoV2 drugs. While drugs are being repurposed and discovered for COVID-19, novel drug delivery systems will be paramount for efficient delivery and avoidance of possible drug resistance. This review describes the proposed drug targets for therapy, and outcomes of clinical trials that have been reported. It also identifies the adopted treatment modalities that are showing promise, and those that have failed as drug candidates. It further highlights various emerging therapies and future strategies for the treatment of COVID-19 and delivery of Anti-SARS-CoV2 drugs. • COVID-19 is a global pandemic that currently has no approved cure and vaccine. 49 • For expedited approval, scientists have turned to repurposing of available drugs in the market 50 in search for a cure. • High volume of emerging therapies for COVID-19 reported so far are demonstrating varying 52 results and need to be compared and evaluated as effective medical options. 53 • Emerging non-conventional drug discovery strategies such as AI and ML show potential for 54 developing alternative drugs for treatment and prevention of COVID-19. 55 The novel coronavirus belongs to the Coronaviridae family of the order Nidovirales which are divided 147 into four genera viz. α, β, γ, and δ. The Coronaviridae family (CoVs) have an outer envelope and the 148 genetic material consists of positive sense RNA (Gorbalenya et al., 2020) . They have been reported to 149 be the largest known viruses with a size of 28-32 kb (Bosch et al., 2003) . The International Committee Coronavirus 2 (SARS-CoV-2) (Gorbalenya et al., 2020) . The SARS-CoV-2 has been identified as 152 belonging to the β genus CoVs family that contains at least four structural proteins (spike, envelope, 153 membrane and nucleocapsid) (Bosch et al., 2003) .WHO named the disease that is caused by SARS- 154 CoV-2 virus as COVID-19. The spikes on the viral surface are composed of homotrimers of the S 155 protein that acts as a link to host receptors. Furthermore, the spike glycoproteins have two subunits, S1 156 and S2, mediating attachment and membrane fusion, respectively. The S2 subunit contains a fusion endothelial cells and smooth muscle cells of various organs (Bavishi et al., 2020) . S protein priming 167 by the serine protease transmembrane protease serine 2 (TMPRSS2) is essential for SARS-CoV-2 168 infection of target cells and spreading throughout the host . 169 The endothelium is arguably the largest 'organ' in the body and this perhaps explains why the viral 170 effects spread to extra-pulmonary organs once it enters the blood circulation. Given that there is such a 171 wide number of targets in the human body, from a pathophysiological approach, it explains why 172 COVID 19 patients present with cardiovascular and other diverse complications (Hamming et al., 173 2004; Zhang et al., 2020b) . Exceptionally high proportion of aberrant coagulation was seen in severe 174 and critical patients with COVID-19, revealing a hypercoagulable state, elevated levels of D-dimer 175 and fibrinogen, near normal activated partial thromboplastin time, with some patients progressing to 176 overt disseminated intravascular coagulation (DIC) . 177 Recent studies investigating the expression of viral entry-associated genes, using single-cell RNA-178 sequencing data from multiple tissues from healthy human donors, have identified transcripts in more 179 tissues and cells, not previously analysed, including its co-expression with TMPRSS2 (Sungnak et al., 180 2020). Importantly, Sungnak, et al, 2020 co-detected these transcripts in specific cells in the 181 respiratory, corneal and intestinal epithelium. Furthermore, they found that these genes are co-182 expressed, in nasal epithelial cells, with genes involved in innate immunity, which impacts upon initial 183 viral infection, spread and clearance. Their work is in accordance with previous studies (Qi et al., 184 2020; Zou et al., 2020) . They found that ACE2 was expressed in cells from airways, cornea, 185 oesophagus, ileum, colon, liver, gallbladder, heart, kidney and testis while TMPRSS2 was highly 186 expressed with a broader distribution, suggesting that ACE2 may be a limiting factor for viral entry at 187 the initial infection stage, rather than TMPRSS2 (Sungnak et al., 2020) . Cells from the respiratory tree, Other manifestations of severe COVID-19 are lymphopenia, disorders of the central or peripheral 221 nervous system, acute cardiac, kidney, and liver injury, in addition to cardiac arrhythmias, 222 rhabdomyolysis, coagulopathy, and shock . Notably SARS-CoV-2 viral load reaches its peak within 5-6 days of symptom onset, and severe 224 COVID-19 cases progress to acute respiratory distress syndrome (ARDS), on average around 8-9 days 225 after symptom onset (Tay et al., 2020) . A timeline for symptoms of the severe disease is described by 226 Berlin et al. 2020. The virus enters the cells via ACE 2, is internalized as described above and triggers a series of events 228 intracellularly, leading to disease manifestation, based on the targeting of key regulatory pathways, 229 cells and organs. However, the main target is the respiratory tree and lung tissue and therefore this will 230 be described in more detail. Notably, the characteristic pulmonary ground glass opacification is seen 231 even in asymptomatic patients (Mason, 2020 with the best support (Mason, 2020) . 236 Tay et al, 2020 describes the chronology of events upon cell entry, describing interaction of SARS-237 CoV-2 with the immune system leading to either a normal 'healthy response' or a dysfunctional 238 immune response (IR). In brief the virus enters the cell (which has both ACE2 and TMPRRSS2), and 239 replicates leading to more viral release. Thereafter, the cell undergoes pyroptosis, and releases An overproduction of pro-inflammatory cytokines, resulting in cytokine storm damages the lung 247 structure and leads to multi-organ damage as it spreads to other parts of the body. The cytokine release 248 syndrome (CRS) or storm is characterized by multiorgan pathology and fever (Lin et al., 2020) . 249 Importantly, non-neutralizing antibodies may further exacerbate organ damage. However, in a healthy 250 immune response, the initial inflammation attracts the following; T cells to the site of infection, The debates concern firstly, a purported upregulation in ACE2 due to ACEI use since their mechanism 337 of action ultimately leads to decreased Ang II, the main effector octapeptide of RAAS. It is widely reported that the host cellular entry involves the endocytic pathway and non-endosomal 370 pathway. Inhibition of the pathway could be a strategy to inhibit the viral entry and infection. Mechanism of the drug targets could include drugs that have the ability to penetrate the lysosomes, However, ivermectin can cross into the brain and react with GABA-gated chlorine channels causing 414 neurotoxicity. This is usually prevented by the blood brain barrier (BBB), particularly by the P- of the cost and a known safety profile due to long usage for malaria treatment but requires intense 439 scientific scrutiny for COVID-19, before use. The immune-modulating activity of CQ was hypothesized to enhance its antiviral effect in vivo. 441 However, its toxicity and side effects such as prolonging QT interval can trigger tachycardias such as The side effects associated with HCQ treatment are still a major cause of concern. On 9th April, the Le identification of suitable drugs will therefore require innovative and superior delivery approaches to 792 maximise their therapeutic efficacy. Nanosystems provide increased drug accumulation at the target 793 site of the disease, increase intracellular penetration, protect drugs from degradation, increase stability 794 and can prevent mechanisms of drug resistance (Fig 3. ). In addition, nanosystems have the ability to For an innate immune response by the body to viruses to be initiated, the cells must have the ability to 840 identify the pathogen trying to invade it. Currently, there are several clinical trials being directed to 841 develop a vaccine, based on several different strategies against SARS-CoV-2 as illustrated in Table 2 . 842 Such approaches include those that target the spike glycoprotein (S protein) as the major inducer of the . SARS-CoV-2 replication circle involves cellular entry which is via fusion and endocytosis, after entry translation occurs as the virus uses host cells enzyme it creates its DNA. This is followed proteolysis then translation to back to RNA after that packaging and viral release occurs. The circles Figure 2 . Network-based methodology combining pharmacology-based network medicine platform to quantify the interplay between the virus-host interactome and drug targets in the human protein-protein interactions network. a Human coronavirus (HCoV) associated host protein sourced from literature and pooled to generate a protein subnetwork. b Network proximity between drug targets and HCoV-associated proteins that were calculated to screen for candidate repurposability. c, d Gene set utilized to validate the network-based prediction. Different drugs can be encapsulated in nanodrug delivery system with ability to specifically target the virus or its infection sites. 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