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Perspectives for Antivirals to Limit SARS-Cov-2 Infection (COVID-19)

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Perspectives for Antivirals to Limit SARS-Cov-2 Infection (COVID-19) MICROBIOLOGY AUSTRALIA, 2021, 42, 47–53 In Focus https://doi.org/10.1071/MA21013 Perspectives for antivirals to limit SARS-CoV-2 infection (COVID-19) Erik De Clercq KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium. Tel.: + 32 16 37 90 20; Email: [email protected] Abstract. Compared with vaccines, antivirals for curbing COVID-19 (SARS-CoV-2 infection) have been developed at a much lower pace. Favipiravir has proven efficacious (in hamsters) but only at a very high dose which may not be feasible in humans. Remdesivir is the sole antiviral approved by the US FDA, but it has not been extensively evaluated for its safety. EIDD-1931 and EIDD-2801 have not been evaluated clinically. Mpro (protease) inhibitors likewise need to be subjected to clinical efficacy and safety studies. Remdesivir is a C-nucleoside and this class of compounds should be further evaluated. Polyanionic substances interfering with virus adsorption to the host cells have not been explored. They may possibly be administered by inhalation. Corticosteroids (such as dexamethasone), while virus-stimulating rather than inhibitory, may counteract the ‘cytokine storm’. Combination of (two or more of) the compounds mentioned above may offer an increased benefit through a synergistic interaction. Received 5 February 2021, accepted 3 March 2021, published online 12 April 2021 Introduction SARS-CoV-2 should be situated in the Coronaviridae (genus: betacoronavirus). The first species to emerge was SARS-CoV-1 Currently, vaccines are more in vogue than antivirals in attempts to (SARS standing for ‘Severe Acute Respiratory Syndrome’)in curb COVID-19. Yet, for vaccines, certain requirements are imper- 2003. Then followed MERS-CoV (MERS: Middle East Respiratory ative, which a fortiori may apply to antivirals as well. These Syndrome) in 2012 and SARS-CoV-2 in 2019 (COVID-19). Poten- requirements follow the rule of 5: effectiveness, safety, availability, tial antivirals against SARS were proposed in 20061 and COVID-19 practicality and costs. in 20202. As the success of vaccination, the use of the vaccinia virus is often cited as responsible for the global (worldwide) eradication of Targets for antivirals (Table 1) the variola virus (smallpox) announced by the World Health Orga- nization (WHO) in 1980. Of all vaccinations, vaccinia is the only Interferon virus vaccine that could be credited with this unique achievement. Interferon was originally discovered in 1957 by Isaacs and Linden- For polio(myelitis) effective vaccines, such as those originally mann3 as a substance produced by the organism to block (‘interfere developed by Jonas Salk and Albert Sabin, have been described, with’) the virus infection, in casu influenza. Over the past decades but the total elimination of the poliovirus, although anticipated, has interferon has been formally approved for the treatment of several still not been achieved. viral infections, including HBV and HCV, despite some undesirable fl For in uenza virus, protective vaccines still have to be adjusted side-effects that are inherently linked to exogenous administration of on an annual basis, and for several other virus infections such as interferon, i.e. fever, fatigue and malaise. yellow fever [the only viral infection for which the discovery of the In the treatment of COVID-19, it may act as a double-edged vaccine was recognised by a Nobel Prize (Max Theiler)], the disease sword. Depending on the host’s responsiveness and the stage of the is still prevalent, as it is transmitted by mosquitos (Aedes Aegypti) disease, interferon (whether a-orb-interferon) might in some and could also originate from an animal reservoir (primates). conditions, because of its antiviral effects, favorably influence the For hepatitis B virus (HBV), both antivirals and vaccines are course of the disease, but being itself a cytokine it might also worsen available, but for other virus infections such as human immunode- the infection by participating in or aggravating the cytokine storm fi ciency virus (HIV), vaccination has (so far) proven unfeasible, or that may accompany the SARS-CoV-2 infection. unnecessary [hepatitis C virus (HCV)], as the use of direct-acting Ribavirin antivirals (DAAs) may be expected to eliminate the virus, or impractical (human rhinoviruses), because there are too many Ribavirin (Virazole) is the first nucleoside analogue ever described serotypes (>100). as a broad-spectrum antiviral agent4. It was reported to be effective Journal Compilation Ó The Authors 2021 Open Access CC BY, published (by CSIRO Publishing) on behalf of the ASM 47 In Focus Table 1. The replicative cycle of SARS-CoV-2 offers several possible targets for chemotherapeutic intervention as does HIV. Target HIV SARS-CoV-2 1. Virus adsorption (attachment) to the host cells Yes Yes 2. Virus penetration into the host cells (for enveloped viruses by fusion) Yes Yes 3. Uncoating (decapsidation) so as to release viral (+)RNA (= mRNA) Yes Yes 4.1. Reverse transcription (+)RNA –> (±)DNA by RNA-dependent DNA polymerase (reverse transcriptase) Yes No 4.2. RNA-dependent RNA polymerase (RdRp) (+)RNA –> (–)RNA –> (+)RNA No Yes 5. Integration of (±) proviral DNA into host cell chromosome Yes No 6. Transcription of proviral (–)DNA to mRNA by cellular DDRp (DNA-dependent RNA polymerase) Yes No 7. Viral mRNA translation to viral proteins Yes Yes 8. Posttranslational modification (proteolytic cleavage by HIV protease, glycosylation, ...) Yes Yes Formation of structural (S) and non-structural (NS) proteins 9. Assembly Yes Yes 10. Budding (release of virus particles) Yes ? in the treatment of Lassa fever (a hemorrhagic fever (HF) arena virus first compound ever shown to block HIV infection, both in vitro14 infection)5. In combination with (pegylated) interferon-a, ribavirin and in vivo15. has been used for almost a full decade (2000-2010) in the treatment Sulfated polysaccharides encompass an extremely wide family of of hepatitis C, where it has now been replaced by the more effective compounds, including natural (marine) substances such as carra- DAAs. geenans derived from seaweeds16. These compounds may be expected Although traditionally regarded as an antiviral agent, its principal to block virus adsorption of all enveloped viruses, including corona- mode of action, the inhibition of the biosynthesis of GTP, conse- viruses. It is surprising that no data have ever been reported on the quently to the inhibition of the IMP dehydrogenase6,isalsocom- activity of any sulfated (or anionic) polymers against SARS-CoV-2. patible with an immunosuppressive effect7. As an antiviral agent, Polyanionic substances may not be suitable for systemic admin- ribavirin may not have sufficient potency to block SARS-CoV-2 istration, as they may not easily reach their target cells upon such replication, but as an immunosuppressant it could exhibit the de- administration, but they could be amenable to topical administration, sirable utility to curtail the cytokine storm accompanying the SARS- i.e. inhalation, which may be well suited in the therapy of SARS- CoV-2 infection. CoV-2 infection. (Hydroxy)chloroquine Protease inhibitors (Hydroxy)chloroquine has been claimed, without any indication of The combination of Lopinavir with Ritonavir (the latter to increase its mode of action, to inhibit SARS-CoV-2 replication in vitro the plasma half-life of the former through inhibition of cytochrome – (hydroxychloroquine being more potent than chloroquine)8 10. P450) has been formally approved as a specificHIVprotease However, Hoffmann et al.definitely ruled out that chloroquine inhibitor duo for the treatment of HIV infections, and so are 8 other could inhibit the replication of SARS-CoV-2 in human lung HIV protease inhibitors (i.e. saquinavir, indinavir, nelfinavir, ampre- (Calu-3) cells11. Also, Kaptein et al.12 found that hydroxychloro- navir, fosamprenavir, atazanavir, tipranavir and darunavir). It is quine was totally inactive against SARS-CoV-2 infections in ham- surprising that Lopinavir and Ritonavir (and later on some other sters. Therefore, there is no compelling reason to further advocate its HIV protease inhibitors) were advocated for the treatment of SARS- use in the treatment of COVID-19. CoV-2 infections. This application has been generated by the fact that Lopinavir and Polyanionic substances Ritonavir were reported to show in vitro inhibitory activity against – For more than half of a century, polyanionic compounds have been SARS-CoV-217 19. It is reassuring therefore that in hospitalised envisaged as potential antiviral agents: i.e. double-stranded RNAs adult patients with severe COVID-19 Lopinavir (+ Ritonavir) treat- such as poly(I).poly(C) as inducers of interferon and sulfated poly- ment did not offer additional benefit beyond standard care20. saccharides such as dextran sulfate as inhibitors of HIV adsorption. The HIV protease is fundamentally different from the corona- The structurally related polysulfonate suramin, originally identified virus main protease Mpro or 3CLpro, which since 2003 has been as a potent (murine) reverse transcriptase (RT) inhibitor13 was the considered as an attractive target for the design of anti-SARS 48 MICROBIOLOGY AUSTRALIA * APRIL 2021 In Focus drugs21. A representative compound, the a-ketoamide 13b (Figure 1) has any therapeutic or prophylactic usefulness against COVID-19 in proved highly effective in inhibiting SARS-CoV-2 replication in humans remains to be determined. 22 human Calu-3 lung cells . This compound might be suitable for RdRp (RNA-dependent RNA polymerase) inhibitors administration by inhalation in the treatment of COVID-19. Besides Mpro, the SARS-CoV-2 RdRp can also be considered as an In general, a-ketoamides display low-micromolar EC50 values fi against a broad range of corona- and enteroviruses23. What remains attractive target in the design of speci c SARS-CoV-2 inhibitors. to be ascertained is whether any of the a-ketoamides, and if so, The structure of this enzyme (nsp12 polymerase bound to nsp7 and 27 which one, has practical utility in the therapy (or prophylaxis) of nsp8 cofactors) was published in 2019 .
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