key: cord-0751383-8l7151mr
authors: Asrani, Purva; Tiwari, Keshav; Eapen, Mathew Suji; McAlinden, Kielan Darcy; Haug, Greg; Johansen, Matt D; Hansbro, Philip M; Flanagan, Katie L; Hassan, Md. Imtaiyaz; Sohal, Sukhwinder Singh
title: Clinical features and mechanistic insights into drug repurposing for combating COVID-19.
date: 2021-11-05
journal: Int J Biochem Cell Biol
DOI: 10.1016/j.biocel.2021.106114
sha: 895b192f7696bc1f560300dca2185b224d63be80
doc_id: 751383
cord_uid: 8l7151mr

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged from Wuhan in China before it spread to the entire globe. It causes coronavirus disease of 2019 (COVID-19) where mostly individuals present mild symptoms, some remain asymptomatic and some show severe lung inflammation and pneumonia in the host through the induction of a marked inflammatory ‘cytokine storm’. New and efficacious vaccines have been developed and put into clinical practice in record time, however, there is a still a need for effective treatments for those who are not vaccinated or remain susceptible to emerging SARS-CoV-2 variant strains. Despite this, effective therapeutic interventions against COVID-19 remain elusive. Here we review potential drugs for COVID-19 classified on the basis of their mode of action. The mechanisms of action of each are discussed in detail to highlight the therapeutic targets that may help in reducing the global pandemic. The review was done up to July 2021 and the data was assessed through the official websites of WHO and CDC for collecting the information on the clinical trials. Moreover, the recent research papers were also assessed for the relevant data. The search was made based on keywords like Coronavirus, SARS-C0V-2, drugs (specific name of the drugs), COVID-19, clinical efficiency, safety profile, side-effects etc.This review outlines potential areas for future research into COVID-19 treatment strategies.

Coronaviruses in the last two decades have caused serious infection and mortality in humans.

In December 2019, a third novel strain of the severe acute respiratory syndrome coronavirus, SARS-CoV-2 surfaced from a seafood market in Wuhan, China. The differences in sequences in the spike protein in SARS-CoV-2 results in its enhanced binding to angiotensin-converting enzyme 2 (ACE2) in human lung cells (Asrani, Hasan et al. 2020) . The greater transmission rates of SARS-CoV-2 as compared to previous coronaviruses, resulted in the infection of >179 million people and 3.8 million deaths across the globe (Organization 2020) . Despite of effective guidelines and safety protocols being released in diagnosis of COVID-19 (Asrani, Afzal Hussain et al. 2021) , worst implications of different waves of COVID-19 were witnessed in many parts of the world including India whose health infrastructure was extremely strained with scarcity of oxygen concentrates and other essential treatment aids (Asrani, Eapen et al. 2021) . Many individuals also struggled to get the diagnosis done through RT-PCR within the specified time putting an undue pressure to the government and health sectors in this time of crisis (Asrani, Eapen et al. 2020 ). This has led to severe global J o u r n a l P r e -p r o o f lockdown causing huge physiological, psychological, social and economic losses to governments and their citizens.

Infection of human airway and lung cells with SARS-CoV-2 results in acute pneumonia-like symptoms and an increased incidence of death among vulnerable older population or those with pre-existing comorbidities such as diabetes, cardiovascular and chronic obstructive pulmonary disease (COPD) (Channappanavar and Perlman 2017; Johansen, Irving et al. 2020 ). Angiotensin-converting enzyme 2 (ACE2) expression is increased in the lower airways of susceptible older and male healthy individuals, while there is reduced expression of ACE2 in patients with asthma (Wark, Pathinayake et al. 2021) . Administration of reninangiotensin aldosterone system inhibitors to the COVID-19 infected patients with history of smoking and comorbidity like COPD should not be encouraged as elevated expression of ACE2 is observed in these cases (Haug, Eapen et al. 2020) . Viruses and other invading microorganisms express multiple pathogen associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors (PRRs) such as toll-like receptors (TLRs), which then elicit inflammatory and innate immune responses in the host (Hansbro, Haw et al. 2017) .

Innate immune responses include the release of inflammatory factors, type I interferons (IFNs) and maturation of macrophages and dendritic cells leading to adaptive immune responses (Lu, Pan et al. 2011) . The SARS-CoV-2 is capable of escaping surveillance by the host innate immune system by either inducing senescence or apoptotic conditions in macrophages or through suppression of interferon type-1 (IFN-1). In the first case, the inflammatory cytokines associated with cellular senescence are produced, which in turn promotes a pro-infectious environment for virus multiplication and subsequent disease manifestations ( Figure 1 ) (Fu, Cheng et al. 2020; Johansen, Irving et al. 2020) . Later, infiltration of immune cells into lung tissue results in the production of more proinflammatory cytokines and reactive oxygen species (ROS) (Asrani and Hassan 2020) .

Secondly, IFN-1 induction plays a central role as an immune defense of the host in response to a viral infection (Stetson and Medzhitov 2006) . Since, production of IFN-β and induction of host antiviral state depends upon activation of a signaling complex located on mitochondrial outer membrane (Liu, Wei et al. 2010) , the ORF9b gene of coronavirus involved in targeting the mitochondria inhibits the production of IFN-1 (Shi, Qi et al. 2014 ).

Adaptive immunity is induced through recognition of viral antigens presented by antigen presenting cells (APCs) to T cell (TCRs) and B cell (BCRs) receptors. In case of SARS, spike J o u r n a l P r e -p r o o f (S) and nucleocapsid (N) protein of coronavirus possesses immunogenic epitopes which are recognized by APCs for inducing humoral immunity. This leads to direct activation of B cells to produce antibodies, as well as activation of CD4+ T helper 2 (Th2) and follicular helper T cells (Tfh) that further activate B cells. CD4+ Th1 cells are also activated to produce proinflammatory cytokines such as IFN-γ (Mortaz, Tabarsi et al. 2020) , and CD4+ Th17 cells that produce IL-17 among other cytokines. Th17 cell activation in SARS-CoV-2 infection leads to increased vascular permeability and leakage. Finally, activated CD8+ cytotoxic T cells (CTL) are able to kill virus-infected cells directly. The two most important antibodies that are produced by B cells includes IgM and IgG. Among these, IgM can be detected after 3-6 days post-viral infection while, IgG could be detected after 8 days of viral infection (Zhuoyue, Xin et al. 2003) . IgG antibodies are more likely to provide protective roles for longer duration as SARS-specific IgM antibodies were found to disappear by the end of week 12 (Li, Chen et al. 2003) . In patients with MERS infection it is suggested that suppression of T cell functionality results in greater production of pro-inflammatory cytokines, free radicals and chemokines in patients; therefore, SARS-CoV-2 is likely to follow a similar destructive pattern affecting lungs and other organs (Niu, Zhang et al. 2018) . Therefore, in later stages of infection, SARS-CoV-2 impacts adaptive immunity by suppressing T cell functions and causing lymphopenia. The exact mechanism behind lymphocyte reduction remains unclear but few hypotheses have been laid in this direction. Some studies supports apoptosis of lymphocytes occurs in patients of severe SARS-CoV-2 infection (Qu, Ling et al. 2020 ) as earlier in case of SARS-CoV-1 acute infection, higher levels of plasma Fas-ligand and cleaved caspase-3-positive CD4 and CD8 lymphocytes were found in patients (Chen, Chang et al. 2006) . Other studies speculate IL-β induced pyroptosis as primary cause of lymphopenia (Tay, Poh et al. 2020) . Other than this, suppression of bone marrow during cytokine storm, direct infection of T-cells with SARS-CoV-2 (Wang, Xu et al. 2020) or during pneumonia, sequestration of immune cells in the infected lung airways could also be probable cause of reduced number of lymphocytes (Azkur, Akdis et al. 2020) .

Post SARS-CoV-2 invasion, downregulation and shedding of ACE2 receptors which leads to loss of renin-angiotensin system (RAS) function has also been observed. Following recovery, COVID-19 occurs with long-term symptoms of breathing difficulty and lethargy which may involve tissue remodelling and fibrosis although this is yet to be confirmed. Some studies J o u r n a l P r e -p r o o f have shown evidence that SARS-CoV-2 promote lung fibrosis by inducing transcriptional signatures in human epithelial cells .

Despite the enormous efforts of researchers to produce anti-viral drugs against COVID-19, the search for an effective treatment has been elusive. Remdesivir, though is not very effective, still has been approved as the first emergency drug for the treatment of in several countries and its extreme shortages necessitates the identification of further treatment options. Here we describe in detail the different drugs that are currently in clinical trials or possess the potential to target specific SARS-CoV-2 infection (Figure 2) . They are classified based on their mode of action and mechanisms. We also describe the previous success of drugs in overcoming other viral and non-viral infections to illustrate their potential for repurposing to combat COVID-19.

Different classes of pharmacological drugs were FDA approved for the treatment of earlier episodes of highly pathogenic human CoVs (Kumari, Singh et al. 2020 (Kindrachuk, Ork et al. 2015) and the neurotransmitter inhibitors chlorphenoxamine (Dyall, Coleman et al. 2014) . In vitro studies with Vero-E6 cell lines infected with mouse-adapted SARS-CoV showed >50% inhibition against the viruses and <30% cytotoxicity by neurotransmitter inhibitors such as chlorpromazine hydrochloride and triflupromazine hydrochloride; kinase inhibitors such as nilotinib; the DNA synthesis inhibitor gemcitabine hydrochloride; and the oestrogen inhibitor toremifene citrate (Dyall, Coleman et al. 2014 ).

Since the distribution of effective vaccines is ongoing, and there will likely be vaccine-escape mutants and people who do not respond or remain unvaccinated there remains an important need to identify effective drugs for treating COVID-19 patients to reduce their viral burden and/or disease severity (Dhama, Sharun et al. 2020) . The WHO has approved various drugs for experimental trials that might become promising agents in treating SARS-CoV-2 infection ( Figure 3) . Furthermore, different classes of other drugs are currently under clinical J o u r n a l P r e -p r o o f investigation to assess their efficacy against COVID-19. These include broad spectrum antivirals, antiretrovirals, antimalarials and antiparasitic drugs, antibiotics, monoclonal antibodies, traditional medicines and immune-modulators and anti-inflammatory drugs (Table 1) . Prevents the formation and polymerization of microtubules. It also inhibits the production of TNF-α from macrophages and prevents their interaction with the endothelial cells required in initiating the process of inflammation.

Gout, arthritis and myocardial infraction.

Inhibits the viral replication and regulates the cytokine storm.

Inhibits the spike protein of SARS-CoV-2 and prevents the viral binding to ACE2 receptors.

Houttuynia cordata Inhibits RdRp and chymotrypsin like protease. It also enhances the effect of CD4 + and CD8 + T cells for inhibiting the replication of virus.

SARS-CoV.

Antiviral drugs specifically aim to target viral entry or replication, or virus-specific enzymes by blocking essential viral factors and cellular processes required for virus survival in the host (Chen-Yu Hsu, Starkey et al. 2015; Durantel and Zoulim 2016) . Here we discuss the mode of action of different antiviral drugs that might have activity against SARS-CoV-2 and describe their targets.

Favipiravir was first authorized in Japan for its activity against influenza virus. The drug is activated upon intracellular phosphoribosylation and then inhibits RNA-dependent RNA J o u r n a l P r e -p r o o f polymerase (RdRp) (Furuta, Komeno et al. 2017) . In a randomized clinical trial, favipiravir was administered to 200 patients with COVID-19 in Wuhan, China. A significant reduction in pneumonia and other COVID-19 symptoms was observed (4 days versus 11 days in the control group). Further, the treated group had a shorter time to negative SARS-CoV-2 PCR result, suggesting that there was a reduced viral load in these patients (Scavone, Brusco et al. 2020 ). The treated group also had a quicker reduction in elevated body temperature (2.5 days versus 4.5 days with placebo) (Chang Chen, Jianying Huang et al.) . Several mechanisms of action are suggested. One is the likely inclusion of the drug into the nascent viral RNA chain or binding into polymerase domains preventing nucleotide incorporation that is required for RNA replication and transcription (Furuta, Komeno et al. 2017) . Another study showed that favipiravir induces a lethal transition mutation of viral RNA nucleotides from C→T or C→U and G →A which might target the viral replication and survival in the host (Baranovich, Wong et al. 2013) .

Ribavirin is an another antiviral drug that blocks viral replication (Crotty, Cameron et al. 2001 ). It is a structural analog of the nucleotide guanosine which interferes with host polymerases that recognize viral RNA and induce replication (Agostini, Andres et al. 2018 ).

This drug also inhibits the enzyme inosine monophosphate dehydrogenase required for the conversion of guanine precursors to guanosine (Markland, McQuaid et al. 2000; Shu and Nair 2008) . With the absence of guanosine residues on the mRNA cap, viral RNA is destabilized leading to its breakdown (Graci and Cameron 2006) . A randomized control trial with ribavirin, 500mg twice (BID) or thrice daily (TID) is recommended in the revised Treatment Plan Edition 5 in China . Ready access and low cost makes Ribavirin the preferred choice over other drugs in this category. However, the use of this drug is controversial, as it induced anemia, depression, insomnia, and irritability in patients infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) (Martin and Jensen 2008) . Hence, the true potential of ribavirin can only be determined in large randomized clinical trials with COVID-19 patients ).

including those caused by Marburg, yellow fever, HCV and Ebola viruses (Rele 2020) . It is a structural analog of adenosine nucleoside and, like Ribavirin, blocks the action of viral RNA polymerase (Taylor, Kotian et al. 2016) . The drug has been demonstrated to be potentially active against some 20 different RNA viruses including those from the families of J o u r n a l P r e -p r o o f coronaviruses, bunyaviruses, togaviruses, filoviruses, arenaviruses, flaviviruses, and paramyxoviruses (Basha 2020; Li and De Clercq 2020) . A dose-dependent inhibition of

conducted with a Vero-E6 cell line (Li, Geng et al. 2020 ). Similar inhibition rates were observed with SARS-CoV-1 (Ataei and Hosseinjani 2020). The high efficiency of this drug against previous CoV outbreaks suggests its potential in treating COVID-19 patients (Zhang, Stephen et al. 2020) . Importantly this drug is well tolerated and can be administered either orally or intramuscularly (Ataei and Hosseinjani 2020) . Larger studies are currently underway to assess the potential of Galidesivir as a therapeutic intervention in COVID-19 (Shah, Modi et al. 2020) .

Nitazoxanide (NTZ), a broad range antiviral drug, is in the thiazolide class of drugs and also has antiparasitic and antibacterial properties (Zumla, Azhar et al. 2015) . It is FDA approved and licensed in the USA, predominantly against gastrointesinal parasites such as Giardia lamblia and Cryptosporidium parvum (Amadi, Mwiya et al. 2002) . In vitro studies with NTZ showed suppressive effects on SARS-CoV-2 replication (Mahmoud, Shitu et al. 2020) , which occurs through interference with host-regulated pathways. These in vitro studies have shown promising results against influenza viruses, HIV and HCV (Rossignol and Keeffe 2008) .

Mechanistically, this drug has been shown to supress various inflammatory cytokines such as IL-2, -4, -5, -6, -8, -10 and TNF-α in peripheral blood mononuclear cells (PBMC) isolated from healthy donors and later cultured in the presence and absence of three different doses of tizoxanide (actively circulating metabolite of NTZ) i.e. 0.5, 1.0 and 10 ng/ml (Clerici, Trabattoni et al. 2011 ). It has been demonstrated that the peak plasma concentration and trough concentration i.e. 4.6 and 0.8 mg/ml of this drug could be achieved in humans during phase 2b/3 clinical trials by twice daily dosing of NTZ controlled release tablets (Rossignol 2016 ). Since, in vitro studies have demonstrated that the low percent inhibitory concentration (IC 50 ) of 0.1 and 1 µg/ml is required to treat influenza and other respiratory viruses therefore, the levels of NTZ achieved in phase 2b/3 clinical trials are sufficient to be used as antiviral therapy of respiratory concern. (Rossignol 2016) . This extended-release tablet holds potential in treating viral respiratory infections by suppressing viral loads and other major symptoms associated with viral entry and replication, such as in influenza (Rossignol 2014) .

Triazavirin (TZV) is another purine nucleoside that inhibits viral replication (Loginova, Borisevich et al. 2014) . Phase 2 clinical trials showed promising results in reducing the J o u r n a l P r e -p r o o f duration of symptoms of influenza (respiratory symptoms and fever) and related complications (pneumonia, diabetes, asthma, lung and heart diseases) associated with secondary influenza virus infections (Kiselev, Deeva et al. 2012 Although no significant difference in time to clinical improvement was recorded, it was noted that the TZV arm had lower frequency of reliance on concomitant medicines for cardiac, renal, respiratory, hepatic and coagulation support (Wu, Yu et al. 2020 ).

Remdesivir, a drug used for the treatment of the Ebola virus and Nipah virus, has also shown some positive effects on the patients with COVID-19 (Wang, Cao et al. 2020) . It is a nucleoside analog possessing antiviral activity (Szychlinska, Castrogiovanni et al. 2019) which works by inhibiting the RNA-dependent RNA polymerase required for the multiplication of virus in lung epithelial cells (Gordon, Tchesnokov et al. 2020) . As an analog of adenine it incorporates itself into the viral RNA and causes premature termination of transcription (Siegel, Hui et al. 2017 showed conversion to a negative PCR result from the start of treatment to 11.3 days in the control group (patients receiving other standard anti-viral treatment) and 4.5 days in the patients belonging to FNC group. Moreover, no adverse effects were recorded during the clinical trial suggesting that larger scale studies are warranted to better analyze FNC"s potential in combating COVID-19 (Ren, Luo et al. 2020 ).

Darunavir (DRV) is another viral protease inhibitor which inhibits the HIV-1 protease and subsequently decreases HIV replication (Rabi, Laird et al. 2013) . It is taken in combination with Cobicistat and Ritonavir which increase its concentration in the plasma (Gallant, Daar et al. 2016) . The tolerability and efficacy of this drug have been proven and therefore, it is licensed drug for HIV patients, suggesting its possible application to COVID-19 patients as well (Orkin, DeJesus et al. 2013) . Also, its adverse side effect profile is minimal. However, recent studies conducted on patients of COVID-19 did not show encouraging results. In a randomized experiment, group 1 received a single pill of DRV/C (800 mg of Darunavir and 150 mg of cobicistat) for 5 days while no oral antiviral drugs were given to the patients of group 2 (control group). It was observed on the fifth day after the treatment, DRV administration did not reduce the duration of conversion to negative PCR compared to controls (Chen, Xia et al. 2020 ). This study was on a pilot scale in which only patients with mild symptoms were enrolled (Chen, Xia et al. 2020) . Similarly, another study reported disappointing results after DRV administration in SARS-CoV-2 patients with pre-existing HIV infection (Riva, Conti et al. 2020 ).

Mefloquine is a quinolone-methanol compound structurally related to quinine. The drug functions against all known malarial parasite types including most drug-resistant forms of Plasmodium falciparum (White 1994) . It functions by inhibiting protein synthesis through its interaction with the 80S ribosome of P. falciparum (Wong, Bai et al. 2017) . In-silico studies and 5 µM respectively). (Gendrot, Duflot et al. 2020) .

Chloroquine (CQ) is a well-established antimalarial drug which has been used for decades.

With respect to SARS-CoV-2 several mechanisms are proposed for the antiviral potential of the drug (Devaux, Rolain et al. 2020). One is interference with the biosynthesis of sialic acid by directly inhibiting the quinone reductase-2 enzyme (Kwiek, Haystead et al. 2004) . Sialic acid plays a significant role in ligand recognition, and CQ may prevent the virus from binding to the cellular sialic acid receptors on the host cell (Varki 1997) . Another mechanism is based on endosome-mediated viral entry into host cells (Gay, Bernard et al. 2012) . Increases in the pH of the endosome prevents the fusion of the viral membrane to the endosome, and, therefore, interferes with viral entry (Vianney, Nguyet et al. 2010) . Similar pH modulations affect the maturation of the viral particles (Randolph, Winkler et al. 1990 ). The accumulation of membrane proteins of SARS-CoV-2 inside Golgi bodies determines the fate of virion budding that may be affected by CQ treatment (Klumperman, Locker et al. 1994) . In vitro studies have demonstrated the activity of CQ against SARS-CoV-2 (Gao, Tian et al. 2020), however it"s administration is strictly controlled in clinical trials because of potential drug interactions and side effects (Hossen, Barek et al. 2020 ).

increasing the pH of endosomes thereby disrupting the fusion of the parasite with the host cell (Savarino, Boelaert et al. 2003 ). It has also been shown that it interferes with the glycosylation of ACE2 receptors (Vincent, Bergeron et al. 2005) . These effects led to the analysis of its potential as a COVID-19 treatment across multiple countries. China followed by France used this drug along with azithromycin and showed positive effects in reducing viral load in COVID-19 patients (Savarino, Boelaert et al. 2003) . In an attempt to treat increasing patient numbers in the USA, the FDA approved its use as a prophylactic agent 

Ivermectin is an antiparasitic drug that also possesses antiviral properties against some viruses. It mainly interferes with the nuclear transport of viral proteins by dissociating importin (IMPα/β1) heterodimers (Wagstaff, Sivakumaran et al. 2012 ). Since nuclear transport is important for the replication of viruses, targeting this process may be a powerful approach against viral infection (Caly, Wagstaff et al. 2012) . Upon exposing SARS-CoV-2 infected vero-hSLAM cells to ivermectin at a concentration of 5µM, a 5,000 fold reduction in SARS-CoV-2 viral activity was reported 48 hours post infection (Caly, Druce et al. 2020 ).

However; Schmith and his team (Schmith, Zhou et al. 2020 ) has shown that the approved concentration of ivermectin as a single drug is not sufficient to reach a successful clinical trial. The total bound and unbound concentrations of plasma ivermectin is still far to reach the IC 50 , even when the level of dose is 10x higher than the approved dose. Therefore, this drug is still under the clinical trials where some studies have shown no benefit including the randomized trials. One of the largest trails of ivermectin showing it to be the most benefit drug against COVID-19 has been retracted because of the falsified data and hence, it has been suggested by Dr. Josh Davis of University of Newcastle to "not to recommend ivermectin for routine use outside the setting of clinical trials".

An FDA-approved anthelminthic drug Niclosamide has also been used against various bacteria, viruses and parasites known to infect humans (Fan, Xu et al. 2019) . It is among the top drugs listed in WHO"s essential medicines (Organization 2019) . It is recommended for use against tapeworms due to its inhibition of oxidative phosphorylation and stimulation of adenosine triphosphatase in mitochondria (Weinbach and GARBUS 1969) . Immunoblot studies with Niclosamide conducted on Vero E6 cells revealed its ability to block viral J o u r n a l P r e -p r o o f replication and abolish antigen synthesis at a concentration of 1.56 µM (Wu, Jan et al. 2004 ).

Moreover, a concentration as low as 1 μM of the drug was sufficient to suppress the cytopathic effect of SARS-CoV-1 in Vero-E6 cell lines with an EC 50 of <0.1 μM (Wen, Kuo et al. 2007 ). Since Niclosamide is an inexpensive and well-tolerated drug it is an attractive candidate for treating COVID-19 in economically poorer countries (Mahmoud, Shitu et al. 2020 ).

Azithromycin is a macrolide antibiotic that interferes with the synthesis of proteins (Sultana, Cutroneo et al. 2020) . It is specifically used to treat respiratory bacterial infections and reduce severity of respiratory symptoms and chronic lung inflammation (Gibson, Yang et al. 2017; Rizk, Kalantar-Zadeh et al. 2020) . It also possesses activity against several respiratory RNA virus infections (Schögler, Kopf et al. 2015) . Several earlier studies support its ability to inhibit Zika virus and rhinovirus replication (Gielen, Johnston et al. 2010) . It also has an in vitro antiviral effect against SARS-CoV-2 (Oldenburg and Doan 2020) and infected bronchial epithelial cells (Gielen, Johnston et al. 2010) . It is a relatively safe and commonly prescribed drug (Oldenburg and Doan 2020) . Some studies suggest that azithromycin, along with HCQ, is efficacious in treating COVID-19 (Gautret, Lagier et al. 2020; Juurlink 2020; Rosenberg, Dufort et al. 2020) ; while others claim that azithromycin activity in COVID-19 is restricted to the inhibition of superimposed bacterial infections rather than direct action against SARS-CoV-2 (Oldenburg and Doan 2020; Sultana, Cutroneo et al. 2020 ). An open label randomized clinical trial in 447 adult participants in Brazil showed no benefit of azithromycin on clinical outcomes including clinical status and mortality in COVID-19 (Furtado, Berwanger et al. 2020 ). This drug is now dropped from the clinical trials because of not being of much clinical importance against COVID-19.

Various other antibacterial drugs have been repurposed as potential therapies for COVID-19 (Karampela and Dalamaga 2020) . The fluoroquinolones including moxifloxacin and levofloxacin are commonly used antibiotics to treat pneumonia (Metlay, Waterer et al. 2019) .

Recent in silico studies showed their ability to bind to the protease of SARS-CoV-2 and thus their potential activity against its replication (Marciniec, Beberok et al. 2020) . with SARS-CoV-2 replication (Enoki, Ishima et al. 2015) . There are few studies of the safety profile and pharmacokinetics of moxifloxacin needed for treatment of lower respiratory tract infections. Notably, other studies highlight that various chronic conditions (cardiac arrhythmias, long term QT prolongation and tendon rupture) are associated with the long term use of quinolones (Cornett, Novitch et al. 2017 ).

Tocilizumab is a monoclonal antibody specifically designed against IL-6 receptors and their signaling pathways (Zhang, Zhao et al. 2020 ). Since IL-6 acts as a ligand for the activation of the JAK-STAT pathway leading to T-helper cells 17 (TH-17) cell differentiation, that can lead to a cytokine storm, blocking the ligand could prevent the signaling cascade that mediates SARS-CoV-2 driven lung inflammation . Clinical studies show encouraging results in patients with COVID-19 including improved oxygenation capacity, reduced respiratory symptoms and fever (Michot, Albiges et al. 2020) . A retrospective analysis of changes in clinical manifestations, laboratory examinations, and CT scan images of 21 patients with severe COVID-19, showed improved recovery and reduced death following the administration of tocilizumab in comparison to the patients who received routine treatment for a week before tocilizumab administration. This routine treatment did not improve the patient"s deteriorating conditions rather led to hypoxemia, sustained fever and worsening of CT scan results and hence, TCZ was given in these patients later to judge its efficacy. It was observed that following TCZ administration, fever returned to normal on the first day and other symptoms reduced within 5 days. The level of supplemental oxygen intake reduced considerably (75%) among 15 out of 20 patients while one patient did not require O 2 therapy. CT scan images showed absorption of lung lesion opacities in 19 patients. The percentage of lymphocytes in peripheral blood returned to normal in 52.6% patients on the fifth day of treatment. On average, patients were discharged ~15 days after tocilizumab treatment (Xu, Han et al. 2020 ). Chinese authorities have approved its use for treating pneumonia associated with COVID-19 and tocilizumab-based therapy has been included in J o u r n a l P r e -p r o o f "Diagnosis and Treatment Program of COVID-19 of the National Health Commission of China" since 3th March 2020 (Fu, Xu et al. 2020) .

Emapalumab is also a monoclonal antibody (IgG1) against IFN-γ (Al-Salama 2019) and is recommended for patients with hyper-inflammatory conditions with multiple organ failure (Locatelli, Jordan et al. 2020) . It has been approved in the US for the treatment of hemophagocytotic lymphohistiocytosis (HLH) disorder. An open label, single group, phase 2-3 study on 34 patients suggested that it is safe in adolescent and pediatric patients suffering from HLH (Locatelli, Jordan et al. 2020 ). Although few clinical trials have been conducted in analyzing the potential of emapamulab to combat COVID-19, the use of Emapalumab in controlling the hyper-inflammation generated upon SARS-CoV-2 replication and through apoptosis and pyroptosis of macrophages is supported (Scala and Pacelli 2020).

Infliximab and Etanercept both inhibit TNF-α, a pro-inflammatory cytokine produced by macrophages during SARS-CoV-2 infection (Kristensen, Saxne et al. 2006 ). Since TNF-α is one of the prominent initial cytokines released during viral infections, it is possible that its active inhibition could diminish the SARS-CoV-2 mediated lung inflammation in host cells (Asrani and Hassan 2020) .

Sarilumab is one of the other antibodies that serves to inhibit the signal transduction by binding to IL-6 receptors both in soluble and membrane bound form. It belongs to the subclass 1 of immunoglobulin G antibody (IgG1). The approval of FDA for its use as anti-RA drug by inhibiting IL-6 signaling suggests their probable use for the patients of COVID-19 (Khiali, Rezagholizadeh et al. 2021) . A prospective study on eight COVID-19 patients in Italy was carried out where all the patients first received a standard anti-viral therapy such as hydroxychloroquine 400 mg, darunavir 800 mg, azithromycin 500 mg, enoxaparin 100 U per kg, cobicistat 150 mg (Benucci, Giannasi et al. 2020 hours and after one week from the first infusion were made. Lymphocyte count, oxygen saturation/fraction of inspired oxygen, IL-6 levels increased in contrary to C-reactive protein, D-dimer, echo score, serum amyloid A and lactate dehydrogenase levels decreased. From the day of hospitalization, seven patients were discharged within the 14 days however; one J o u r n a l P r e -p r o o f patient did not show improvement in the oxygen saturation and died on the 13 th day. A mild increase in the IL-6 levels occurred because of decreased IL-6 clearance after massive blockage of IL-6 receptors by this antibody.

Anakinra blocks IL-1 receptors and the synthesis of IL-1β and IL-1α, two stimulatory cytokines produced by macrophages to initiate the inflammation cycle (Zeng, Yu et al. 2020) that are oftenly associated with severe respiratory diseases like asthma, chronic obstructive pulmonary diseases (COPD) including COVID-19 (Kim, Pinkerton et al. 2015 {Kim, 2017 Kim, Pinkerton et al. 2017) .

A small scale open label study of the efficacy of anakinra showed improvement in the oxygenation capacity and reduced the need for life-saving mechanical ventilation in COVID-19 patients in comparison to the patients before treatment (Aouba, Baldolli et al. 2020) . It is administered by subcutaneous injection and sometimes induces a reaction at the injection site limiting its use (Ramírez and Cañete 2018) . Some studies show serious side-effects with predisposition to infections like pneumonia, gangrene, cellulitis and herpes zoster virus with high dose (>100 mg) treatment for rheumatoid arthritis. (Salliot, Dougados et al. 2009 ). The German National Registry (RABBIT) showed that adverse effects linked with the administration of anakinra occur at a rate of 17.5/100 patient years while serious adverse events occurred at 3.2/100 patient years (Lampropoulos, Orfanos et al. 2015) . Since, no serious side effects are associated with its use however; determination of optimal concentration of this drug along with close monitoring of patients is required before this could be repurposed in the treatment of COVID-19. (Aouba, Baldolli et al. 2020) .

Colchicine is an anti-inflammatory drug recommended for the treatment of gout and arthritis (Tardif, Kouz et al. 2019 ). Its potential is currently being explored for treating COVID-19 (Schlesinger, Firestein et al. 2020) . Low dose colchicine prevents the formation of microtubules required for mitosis and higher doses prevent microtubule polymerization (Bhattacharyya, Panda et al. 2008) . Since microtubules play a significant role in the maintenance of cell shape, motility, cell signaling, and signal transduction, several important cellular processes are targeted at once (Ben-Chetrit and Levy 1998). It also possesses antiinflammatory effects on neutrophils by reducing the expression of adhesion molecules, motility and migration, thereby interfering with their interactions with endothelial cells (Li, Davis et al. 1996) . It also inhibits the production of TNF-α by macrophages required to J o u r n a l P r e -p r o o f initiate inflammatory processes and prevents their interaction with the endothelial cells (Ding, Porteu et al. 1990 ). Coronaviruses use tubulins to enter into host cells and microtubules during their replication cycle (Sims, Burkett et al. 2008) . Various other traditional herbs from different geographical locations are being studied to identify their potential role in treating COVID-19 (Mirzaie, Halaji et al. 2020) .

Microorganisms also play an important role in modulating plant bioactive compounds for metabolic and immune fitness (Shinde, Hansbro et al. 2020 ). Plants such as Pyrrosia lingua, Lindera aggregata, Lycoris radiata, and Artemisia annua showed anti-SARS-CoV-1 activity at 2.4-88.2 μg/mL (Li, Chen et al. 2005 cytotoxic concentration (CC 50 ) value of 1498.0±912.0mM in cytotoxicity assay and selective index greater than 900. This supports its use as an excellent candidate for anti-viral activity (Lau, Lee et al. 2008) . Other medicinal compounds like Polygonum multiflorum and Rheum officinale inhibit interactions of the spike protein of SARS-CoV-1 and prevents its binding to ACE2 receptors (Ho, Wu et al. 2007) . Aqueous extract of the traditional herb Houttuynia cordata inhibits RNA-dependent RNA polymerase (RdRp) and chymotrypsin-like protease from SARS-CoV-1 (Luo, Wang et al. 2019) . It also enhances the ability of CD4 + and CD8 + T cells to inhibit the replication of viruses (Chiow, Phoon et al. 2016) . These traditional herbs are hypothesized to possess similar antiviral effects against SARS-CoV-2 owning to high similarity with SARS-CoV-1 (Nugraha, Ridwansyah et al. 2020 ).

General health and well-being is important to prevent or tackle the widespread diseases by naturally boosting the immunity of an individual (Kurian, Unnikrishnan et al. 2021) . From past, the concept of probiotics and prebiotics have continued to shape the lives of individuals J o u r n a l P r e -p r o o f and are common household items which are taken in different forms for maintaining a good health.

Probiotics consists of live microorganisms which when administered orally benefits the human health by reconstituting the composition of gut microbiota (Gohil, Samson et al. 2021 ). The close association of gastrointestinal and respiratory system has also been established suggesting the alternative way of treating the infections of respiratory origin (Spagnolello, Pinacchio et al. 2021) . A bidirectional communication between gut and lung referred to as gut-lung axis has been evident which is strongly associated with immune homeostasis (Dang and Marsland 2019; Olaimat, Aolymat et al. 2020) .

Four clinical trials have been found to have the positive results when probiotics were used as an adjunctive treatment in COVID-19. One of the study has shown a misbalance of certain essential microbial population such as Lactobacillus and Bifidobacterium in the intestine of the COVID-19 patients and therefore, probiotics could potentially aid in restoration of these natural microbial populations (Xu, Cai et al. 2020) . Another study emphasized that the large dose of probiotics helped in dissolving the symptoms associated with COVID-19 accompanied by reduction in the signs of inflammation (Wu, Xu et al. 2020 ).

There are number of ways through which probiotics work. They remodulate the microbial flora in the gut and prevent the entry of pathogenic microorganisms (Peng, Zhang et al. 2021) . Probiotics bind to the gut epithelium and undergo competitive inhibition with the pathogens who enter via gut route (Walton, Gibson et al. 2021) . They may release substances that modulates the permeability of intestine (Weiland-Bräuer, Pinnow et al. 2020{Ceccarelli, 2020 . Some probiotics may result in secretion of mucin which forms a mucus layer as a part of first line defence against invading microorganisms (Din, Mazhar et al. 2020) . They are also know to function by strengthening the epithelial barrier and in attenuating the signs of inflammation (Hiippala, Jouhten et al. 2018 ).

An another approach called bioengineered probiotic has been proposed by Verma et al., 2019 (Verma, Xu et al. 2019 where Lactobacillus paracasei (LP) expressing secretory human ACE2 (in fusion with the non-toxin subunit B of cholera toxin) was used as a live vector for oral delivery of human ACE2. The validation of this probiotic was performed in the mouse model of diabetic retinopathy. The successful implementation of this bioengineered J o u r n a l P r e -p r o o f technology has also indicated its possible use for preventing the COVID-19. Apart from interfering with the entry of SARS-CoV-2, these probiotics might boosts an innate immunity or might be useful in controlling the dysbiosis in COVID-19 patient (Senapati, Dash et al. 2020 ).

The alarming rate of occurrence of COVID-19 in different countries underscores the urgent need for effective treatments. Different classes of drugs have shown promise in treating SARS-CoV-2 infection and COVID-19 in small-scale studies. However, larger well-powered randomized controlled clinical trials are required to ensure their safety and efficacy. Even as vaccines become widely available throughout the world, SARS-CoV-2 is here to stay and cases will continue to present, therefore the quest for effective treatments remains imperative. J o u r n a l P r e -p r o o f

Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease

Emapalumab: first global approval

Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial

Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series

Guidelines and safety considerations in the laboratory diagnosis of SARS-CoV-2 infection: A prerequisite study for health professionals

Diagnostic approaches in COVID-19: clinical updates

Implications of the second wave of COVID-19 in India

Molecular basis of pathogenesis of coronaviruses: a comparative genomics approach to planetary health to prevent zoonotic outbreaks in the 21st century

SARS-CoV-2 mediated lung inflammatory responses in host: targeting the cytokine storm for therapeutic interventions

Production of Fermented Beverages: Shedding Light on Indian Culture and Traditions. Production and Management of Beverages

Molecular Mechanisms of Galidesivir as a Potential Antiviral Treatment for COVID-19

Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19

T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro

Corona virus drugs-a brief overview of past, present and future

Colchicine: 1998 update

COVID-19 pneumonia treated with sarilumab: a clinical series of eight patients

Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin

Coronavirus genome structure and replication. Coronavirus replication and reverse genetics

The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

Nuclear trafficking of proteins from RNA viruses: potential target for antivirals?

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

Targeting PI3K-p110α suppresses influenza virus infection in chronic obstructive pulmonary disease

Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies

First clinical study using HCV protease inhibitor danoprevir to treat naive and experienced COVID-19 patients

Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19

Role of vascular cell adhesion molecules and leukocyte apoptosis in the lymphopenia and thrombocytopenia of patients with severe acute respiratory syndrome (SARS)

Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection

The anti-infective Nitazoxanide shows strong immumodulating effects (155.21)

Macrolide and fluoroquinolone mediated cardiac arrhythmias: clinical considerations and comprehensive review

RNA virus error catastrophe: direct molecular test by using ribavirin

Microbes, metabolites, and the gut-lung axis

COVID-19) infections

Pleiotropic effects of levofloxacin, fluoroquinolone antibiotics, against influenza virus-induced lung injury

Dual activity of niclosamide to suppress replication of integrated HIV-1 and Mycobacterium tuberculosis (Beijing)

Hydroxychloroquine for COVID-19: What do the clinical trials tell us

Why tocilizumab could be an effective treatment for severe COVID-19?

Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

pH-dependent entry of chikungunya virus into Aedes albopictus cells

Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: In vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate

Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial

Azithromycin induces anti-viral responses in bronchial epithelial cells

Probiotics in the prophylaxis of COVID-19: something is better than nothing

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Mechanisms of action of ribavirin against distinct viruses

Toll-like receptors in COPD

Renin-Angiotensin-Aldosterone System Inhibitors in Covid-19

The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation

Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction

A Review on Current Repurposing Drugs for the Treatment of COVID-19: Reality and Challenges

Animal and translational models of SARS-CoV-2 infection and COVID-19

Hydroxychloroquine in the prevention of COVID-19 mortality

Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection

Could Respiratory Fluoroquinolones, Levofloxacin and Moxifloxacin, Prove to be Beneficial as an Adjunct Treatment in COVID-19?

Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19

Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19

A comprehensive review on sarilumab in COVID-19

Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma

Inflammasomes in COPD and neutrophilic asthma

Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis

A new antiviral drug triazavirin: results of phase II clinical trial

Coronavirus M proteins accumulate in the Golgi complex beyond the site of virion budding

Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden

Potential diagnostics and therapeutic approaches in COVID-19

Probiotics in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects

Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines

Adverse events and infections in patients with rheumatoid arthritis treated with conventional drugs or biologic agents: a real world study

Immunomodulatory and anti-SARS activities of Houttuynia cordata

Profile of specific antibodies to the SARS-associated coronavirus

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

Identification of natural compounds with antiviral activities against SARS-associated coronavirus

Molecular immune pathogenesis and diagnosis of COVID-19

Inhibition of LPS-induced tumor necrosis factor-α production by colchicine and other microtubule disrupting drugs

Tom70 mediates activation of interferon regulatory factor 3 on mitochondria

Emapalumab in children with primary hemophagocytic lymphohistiocytosis

Investigation of triazavirin antiviral activity against tick-borne encephalitis pathogen in cell culture

SARS-CoV nucleocapsid protein antagonizes IFN-β response by targeting initial step of IFN-β induction pathway, and its C-terminal region is critical for the antagonism

Application of Chinese medicine in acute and critical medical conditions

Remdesivir for the Treatment of Covid-19-Final Report

Drug repurposing of nitazoxanide: can it be an effective therapy for COVID-19?

Ciprofloxacin and moxifloxacin could interact with SARS-CoV-2 protease: preliminary in silico analysis

Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon

Ribavirin in the treatment of chronic hepatitis C

Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the

Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-19-related respiratory failure: a case report

A narrative literature review on traditional medicine options for treatment of corona virus disease 2019 (COVID-19)

No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection

The immune response and immunopathology of COVID-19

Discovery of 4′-azido-2′-deoxy-2′-C-methyl cytidine and prodrugs thereof: A potent inhibitor of Hepatitis C virus replication

Ultrapotent human neutralizing antibody repertoires against Middle East respiratory syndrome coronavirus from a recovered patient

Traditional herbal medicine candidates as complementary treatments for COVID-19: A Review of Their Mechanisms, Pros and Cons

The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19

Azithromycin for severe COVID-19

World Health Organization model list of essential medicines: 21st list 2019, World Health Organization

WHO coronavirus disease (COVID-19) dashboard

Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatmentnaive patients in the ARTEMIS trial

Probiotics as Adjunctive Treatment for Patients Contracted COVID-19: Current Understanding and Future Needs

Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

Anakinra for the treatment of rheumatoid arthritis: a safety evaluation

Acidotropic amines inhibit proteolytic processing of flavivirus prM protein

Emerging outbreaks and epidemic threats: The practicality and limitations in the development and manufacturing of treatments for Coronavirus (COVID-19)

A Randomized, Open-Label, Controlled Clinical Trial of Azvudine Tablets in the Treatment of Mild and Common COVID-19, a Pilot Study

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform

Darunavir does not prevent SARS-CoV-2 infection in HIV patients

Pharmaco-immunomodulatory therapy in COVID-19

Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state

Nitazoxanide: a first-in-class broad-spectrum antiviral agent

Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus

Thiazolides: a new class of drugs for the treatment of chronic hepatitis B and C

Lianhuaqingwen exerts anti-viral and antiinflammatory activity against novel coronavirus (SARS-CoV-2)

In silico Potential of Approved Antimalarial Drugs for Repurposing Against COVID-19

Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials

Effects of chloroquine on viral infections: an old drug against today's diseases

Fighting the Host Reaction to SARS-COv-2 in Critically Ill Patients: The Possible Contribution of Off-Label Drugs

Current pharmacological treatments for COVID-19: What's next?

Colchicine in COVID-19: an Old Drug, New Use

The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19

Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells

Bioengineered probiotics to control SARS-CoV-2 infection

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

COVID-19 infection: origin, transmission, and characteristics of human coronaviruses

SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome

Microbiota modulating nutritional approaches to countering the effects of viral respiratory infections including SARS-CoV-2 through promoting metabolic and immune fitness with probiotics and plant bioactives

Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery

Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo

SARS-CoV replication and pathogenesis in an in vitro model of the human conducting airway epithelium

Targeting microbiome: an alternative strategy for fighting SARS-Cov-2 infection

Type I interferons in host defense

Azithromycin in COVID-19 Patients: Pharmacological Mechanism, Clinical Evidence and Prescribing Guidelines

Physical activity and Mediterranean diet based on olive tree phenolic compounds from two different geographical areas have protective effects on early osteoarthritis, muscle atrophy and hepatic steatosis

Efficacy and safety of low-dose colchicine after myocardial infarction

The trinity of COVID-19: immunity, inflammation and intervention

BCX4430-a broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease

First Long-Term Behavioral Records from Cuvier"s Beaked Whales (Ziphius cavirostris) Reveal Record-Breaking Dives

Sialic acids as ligands in recognition phenomena

Expression of human ACE2 in Lactobacillus and beneficial effects in diabetic retinopathy in mice

A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Mechanisms linking the human gut microbiome to prophylactic and treatment strategies for COVID-19

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drugresistant strains than lamivudine in vitro

SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion

ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma

The Native Microbiome is Crucial for Offspring Generation and Fitness of Aurelia aurita

Mechanism of action of reagents that uncouple oxidative phosphorylation

Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus

Mefloquine

Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis

Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide

The volatile and heterogenous gut microbiota shifts of COVID-19 patients over the course of a probiotics-assisted therapy

Efficacy and safety of triazavirin therapy for coronavirus disease 2019: A pilot randomized controlled trial

SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis

Management of COVID-19: the Zhejiang experience

The pyrimidine analog FNC potently inhibits the replication of multiple enteroviruses

Effective treatment of severe COVID-19 patients with tocilizumab

Effect of convalescent plasma therapy on viral shedding and survival in patients with coronavirus disease 2019

The epidemiology, diagnosis and treatment of COVID-19

Novel Coronavirus Polymerase and Nucleotidyl-Transferase Structures: Potential to Target New Outbreaks

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China

Novel nucleoside analogue FNC is effective against both wild-type and lamivudine-resistant HBV clinical isolates

IFA in testing specific antibody of SARS coronavirus

Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections