key: cord-1032552-v06heov5 authors: Subramaniam, Mohana Devi; Venkatesan, Dhivya; Iyer, Mahalaxmi; Subbarayan, Sarathbabu; Govindasami, Vivekanandhan; Roy, Ayan; Narayanasamy, Arul; Kamalakannan, Siva; Gopalakrishnan, Abilash Valsala; Thangarasu, Raviminickam; Kumar, Nachimuthu Senthil; Vellingiri, Balachandar title: Biosurfactants and anti-inflammatory activity: A potential new approach towards COVID-19 date: 2020-09-30 journal: Curr Opin Environ Sci Health DOI: 10.1016/j.coesh.2020.09.002 sha: 0ed11eed3dbb0cbff1ceccb2a0ec64999fc57ddd doc_id: 1032552 cord_uid: v06heov5 Coronavirus Disease 2019 (COVID-19) has grown to be global public health emergency. The biosurfactants (BSs) are surface-active biomolecules with unique properties and wide applications. Several microbes synthesize secondary metabolites with surface-active properties which has wide range of anti-inflammatory and anti-viral role.. The monocytes and neutrophils are activated by bacteria which subsequently result in high secretion of pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-12, Il-18 and IL-1β) and toll-like receptors-2 (TLR-2). Following the inflammatory response, BSs induce the production of cationic proteins, reactive oxygen species (ROS) and lysozyme, and thus can be utilized for therapeutic purposes. This review provides recent advances in the anti-inflammatory and antiviral activities of biosurfactants and discusses the potential use of these compounds against COVID-19, highlighting the need for in-vitro and in-vivo approaches to confirm this hypothesis. This suggestion is necessary because there are still no studies that have focused on the use of biosurfactants against COVID-19. Surfactants are molecules with amphipathic properties having hydrophilic and hydrophobic moieties that reduce surface and interfacial tension between liquids or biphasic systems as liquid / gas, liquid / liquid and solid / liquid. Based on the origin, the surfactants have been classified into chemical surfactants and biosurfactants (BSs) [1] . BSs are secondary metabolites obtained from several microorganisms including bacteria, fungi and yeasts; classified based on their chemical composition and their origin from microbes, including Pseudomonas aeruginosa, Bacillus subtilis and Lactobacillus sp. [2] . They are attached either intracellularly or extracellularly during growth [3] . BSs are used in a wide range of applications since it is eco-friendly and biodegradable than synthetic surfactants. In recent years this has attracted broad interest due to their unique properties like specificity, low toxicity and smooth preparation. These properties have gained attention in broad areas of cleaning and other applications for commercialization [4] . The unique features of BS opted for industrial applications such as petroleum, fertilizers, cosmetics, chemicals, foods, pharmaceuticals and more. They are also used as emulsifiers, demulsifiers, foaming agents, food ingredients and detergents. Generally, the BSs are used in hand washes and for personal hygiene purposes in order to prevent the viral transmission, get rid of viral disease symptoms, acts as drug transport and also as anti-viral facemasks [4] . An essential property of BS is the surface and interfacial tension. Surface tension is defined as the tension created between attractive intermolecular forces in a molecule. The ability to minimize the surface tension determined by the concentration of the surface-active compound called critical micelle concentration (CMC). The CMC is the minimum concentration required to reduce the surface tension and induce micelle formation. The primary function of BS is to control the attachment and detachment of microorganisms from the surfaces [5] . The structure of BS depends upon the presence of hydrophobic and hydrophilic moieties. Hydrophilic moiety consists of peptides, amino acids, mono-, di-and polysaccharides, whereas hydrophobic consist of saturated and unsaturated fatty acids. The BS are differentiated based on molecular mass were the lower molecular mass molecules reduce the surface, and interfacial tension and the higher molecular weight efficiently function as emulsion balancing agents. Based on molecular mass the BSs are classified as glycolipids, phospholipid, lipoprotein or lipopeptide, polysaccharide-lipid complex or microbial cell surface. Microorganisms also produce chemicalbased surfactants known as polymeric microbial surfactants (PMS). Hence, the physiochemical J o u r n a l P r e -p r o o f properties of BSs and their biomedical applications with the source and chemical structure have been distinguished. The classification of BSs from various organisms and studies with biomedical importance has been tabulated in Table 1 . Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus emerged in December 2019 and became a global pandemic. The COVID-19 has grown to be a global public-health emergency [6] . The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new member of the genus beta coronavirus which exhibits faster human to human transmission leading to a world-wide public health emergency [7, 8] . Once infected, the patient mainly relies on the immune system to resist SARS-CoV-2, with the supportive treatment being prescribed if complications occur [9] . Meanwhile, scientists confirmed that the first step in the SARS-CoV-2 pathogenesis is the specific interaction of the virus with angiotensin-converting enzyme 2 (ACE2), a master regulator of the renin-angiotensin system (RAS) of host cells through its spike protein [10]. Once the virus enters the lungs, the immune system sends a large number of immune cells to kill the virus [11] . Once the cytokine storm is formed, the immune system is exaggerated and kills the healthy cells [12] . Besides, the ability of the virus to evade, the immune system is hugely problematic when considering appropriate treatment and vaccine options. SARS-CoV-2 debilitates the equilibrium maintained by the immune system and triggers the cytokine storm. The significant difficulties found in COVID-19 patients have been linked to the cytokine storm. In-depth research is required to effectively manage the cytokine storm while maintaining the immune system balance. Upon binding, the spike protein is cleaved into two and this induces a conformational change facilitating the fusion of the virus and its entry into the cell. Recently, Vellingiri et al. [6] comprehensively discussed about the viral transcription, translation and expression of viral proteins in the cells. BSs in medical application has elevated during the past decade. BS acts as a therapeutic agent due to its anti-viral, anti-bacterial and anti-fungal property in fighting many diseases [13] . Hence this review focuses on the anti-inflammatory and anti-viral properties of the BSs and its potential uses against as a strategy to treat or prevent COVID-19 disease. indicate that SLs would be a promising therapy for anti-inflammatory or immunomodulation in chronic inflammatory conditions. MELs are secreted by Pseudomonas antarctica, which has also inhibited the inflammatory mediators, thereby creating anti-inflammatory action [29] . From these studies, it is clarified that the BSs from bacterial and yeast species showed an anti-inflammatory J o u r n a l P r e -p r o o f activity and suggested to be potential therapeutic candidate in treating inflammatory diseases. Also, more studies need to be conducted on the effects of anti-inflammation using these BSs. Once the SARS-CoV-2 enters the human host cell through the ACE2 receptors, When additional signals like increased Ca 2+ and ROS are detected, the pro-IL-1β and procaspase 1 are cleaved into IL-1β and caspase 1. This results in the production of cytokines such as (TNF-J o u r n a l P r e -p r o o f α, IL-1B, IL-6, IL-2) and causes a cytokine storm that results in necrosis and cell death. In COVID-19 patients it is observed that there is an inhibition in the production of heme, as it is responsible for the production of biliverdin, ferrous iron and carbon mono-oxide which could limit the inflammation and stress caused due to SARS-CoV-2 viral infection [37] [38] [39] . If the BS is provided to the COVID-19 patients, then it could suppress the production of NF-κB by stimulating the HO-1 and TH1 macrophage cells [40] . This, in turn, would reduce the production of cytokines such as TNF-α, IL-1B, IL-6, IL-2, which will reduce the effect of cytokine storm in the COVID-19 patients. This possible mechanism has been depicted in Figure 1 . Even it has been reported that as the BSs are known for its emulsification role in drugs or vaccines would be highly successful as they are produced naturally which contains non-toxic and non-pyrogenic immunological adjuvants when mixed with conventional antigens for treating COVID-19 disease [41] . Hence these pieces of evidence show that BSs play a huge role as immunosuppressive agents and could be highly used as a combinational drug to relieve inflammatory responses caused due to SARS-CoV-2 infection. Certain BSs inactivates viruses due to physio-chemical reactions [42] . This hypothetical nature occurs only in enveloped viruses. Generally, it is stated that BSs disturbs the viral membrane structures and disrupts the outer covering [27] . The hydrophilic nature of the BS occurs due to the presence of acetyl groups that promotes anti-viral activity [43] . Also, the hydrophobic nature with specific number of carbon atoms inactivates the virucidal effects [44] . High inactivation arises when the BS has a fatty acid chain with 15 carbon atoms and one negative charge; in addition, monomethyl esters showed viral inactivation in semliki forest virus [44] . The antiviral activity of BSs have been approved and patents obtained on treating various viruses [45] [46] [47] [48] [49] . Evidential reports from these studies can be applied in SARS-CoV-2 since it is an enveloped virus hence the mechanism of action has been explained as follows. As the SARS-CoV-2 virus enters the host cell, the amphiphilic nature of BSs interacts with viral cell membrane and enters the bilayered lipid membrane that causes changes in permeability either by ion channel formation or disruption of the membrane system. A complete disintegration of the viral envelope and capsid protein occurs during high concentration of BSs. The disruptions of the lipid envelope and spike protein are encapsulated into micelles and results J o u r n a l P r e -p r o o f in viral inactivity. This micelle formation has the capability to function as liposomes that could deliver the drug to the infection site and also protects during hazardous conditions [50] . Hence, the nature of BSs to form as micelles would be an effective drug delivery system in treating SARS-CoV-2 infection. Also, BS does not affect the viral replication but inactivates the viral effects before adsorption or penetration. The mechanism of anti-viral activity by BS against SARS-CoV-2 is described in Figure 2 . The COVID-19 disease, which is spreading vigorously, has become a global threat across the world. Discovery of any medicine or vaccine against this disease will be a kingmaker for the people suffering from this deadly infection. Hence, here we are recommending few products which will be produced using BS as a more potent way to get precautions or treatment from the SARS-CoV-2 infection. The following guidelines are; • The BS has multi-purpose use in various fields such as food, pharmacology, cosmetics, detergents and so on. But its anti-inflammatory property would be a novel solution in targeting COVID-19 disease in multiple ways. • As always, cleaning our hands will protect us from this virus. The strategy of employing BS encoded handwash or hand sanitizers promises to be a more protective shield against SARS-CoV-2 virus. • The amphiphilic nature of the BS makes it easier to interact with SARS-CoV-2's lipid bilayer and would enable the destruction of the viral genome, which would facilitate easy clearance of the virus. • The propensity of BSs towards drug delivery is high, especially due to its emulsification property. • Hence it is highly advisable that using or producing any drug from BSs along with conventional drugs or vaccines for COVID-19 will be beneficial because of its anti-viral and anti-inflammatory role against the SARS-CoV-2 virus. • The list of clinical trials and ongoing trials about BSs as drugs against various respiratory disorders as well as for COVID-19 have been depicted in Table 2 . • As it is evident that BSs are eco-friendly and less toxic, it is recommended that its use in house-hold cleaning products or detergents will target and kill the SARS-CoV-2 virus. • Another way of incorporating the BS in targeting the virus is its use as a medicated chewing gum. • Incorporation of the BSs from microbes along with Indian medicinal plants promises to be highly instrumental in clearing the viral load efficiently from the human body. Immunologists are working relentlessly to determine the immunity against SARS-CoV-2 and how long it might last [51] . Tremendous effort has been focused on neutralizing the antibodies which bind to the viral proteins which directly prevent infection. Studies found that levels of neutralizing antibodies against SARS-CoV-2 remain high for a few weeks after infection but then typically begin to wane. Various therapeutic approaches have been recently discussed for COVID-19 [52] . Recently, there is an increased attention of BSs as therapeutic agents, due to their immunosuppressive potential and as a novel treatment molecule in most of the immune diseases. Scientists are working very hard for the best protection to the public before a vaccine is being made available [53] . Microorganisms can synthesize a high number of BSs at industrial scale, and these BSs from the microbial source could be anew move towards COVID-19, and this kind of study are warranted at this current scenario to combat the pandemic situation. The above image depicts the hypothetical role of BSs as anti-inflammatory agents against COVID-19. When the SARS-CoV-2 enters the cell, it binds to the ACE2 receptor following which the TMPRSS2 helps in the cleavage of S protein into S1 and S2 subunits. Subsequently, the viral replication gets initiated resulting into NF-κB pathway, which stimulates the release of cytokine storm. In this condition, providing the COVID-19 patients with BSs along with other drugs promises to suppress the production of NF-κB by triggering the heme-oxidase 1 and TH1 macrophages, which in turn would reduce the effect of cytokine storm and inflammation in the COVID-19 affected patients. Production and characterization of a biosurfactant produced by Streptomyces sp. 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