5. Conclusions
The life cycle of SARS-CoV-2 can be divided into two phases. On the one hand, events prior to the viral RNA replication represent the early stage of the virus life cycle. This stage involves the binding of the virus to the host cell receptor, its membrane fusion with the host cell membrane, clathrin-mediated endocytosis, and the release of the viral genome into the host cytoplasmic environment. On the other hand, events that involve RNA replication and subsequent processes represent the later stage of the virus life cycle. Specifically, it entails the RNA replication process, viral protein synthesis and processing, and viral particle assembly, and mature virus release. Notably, events in the two phases are mediated by several interactions among various viral and host proteins. For example, the viral entry is initially mediated by interactions between the viral spike S protein and the host cell receptor ACE2. Furin, TMPRSS2, and cathepsin L enzymes are also important for the early stage of the viral infection. Importantly, the later stage of the viral life cycle involves a different set of virus–host interactions that are mediated by a different set of enzymes. For example, the virus genetic material replication is catalyzed by RdRp and requires nucleotides that are provided by the host cell and biosynthesized by enzymes such as inosine monophosphate dehydrogenase and dihydroorotate dehydrogenase. Furthermore, the resulting viral proteins require further processing which takes place by the action of by Mpro and PLpro.
Importantly, any of the virus or the host proteins and the associated events can serve as a potential drug target for the design and development of anti-COVID-19 therapeutics. We previously reviewed potential anti-COVID-19 therapeutics that target the early stage in the viral life cycle [12]. In this review, we summarized potential therapeutics that interfere with the post-entry events of the viral cycle. Important molecular targets to be considered here are the viral RNA polymerase, the viral processing Mpro and PLpro enzymes, and the host dihydroorotate dehydrogenase. In this arena, we described potential therapeutics that are currently listed in clinicaltrials.gov. These include small molecule drugs such as nucleoside-based antivirals (galidesivir, ribavirin, clevudine, emtricitabine, and EIDD-2801), nucleotide-based antivirals, (remdesivir, tenofovir, and AT-527), arylpropanol-based peptidomimetics (lopinavir, ritonavir, and others), NSAIDs (indomethacin and naproxen), inhaled nitric oxide, polyalcohol natural products (resveratrol and quercetin), antiprotozoal and antimalarial drugs (nitazoxanide, levamisole, atovaquone, and artesunate), cyclic and acyclic natural peptides (deferoxamine, plitidepsin, and cyclosporine A), and a few others. The case of favipiravir is also unique as it is a non-nucleoside(tide) drug, yet it gets subsequently activated to the corresponding active form of favipiravir-ribose-triphosphate. The described therapeutics also include macromolecules such as thymalfasin, lactoferrin, TY027, and XAV-19.
Many of the above drugs are currently approved therapeutics for other indications; thus, they present a unique repurposing opportunity. Yet, others are new molecular entities such as AR-527, EIDD-2801, ACS-09, vidofludimus, VERU-111, and BLD-2660. Interestingly, the reviewed therapeutics exploit a range of mechanisms which will essentially enhance the likelihood of obtaining effective therapeutics in a timely manner. Furthermore, many of the presented therapeutics promote pharmacological effects beyond the antiviral effects. Of note are the anti-inflammatory/immune-modulatory effects of selinexor, NSAIDs, VERU-111, leflunomide, and BLD-2660. These effects are of enormous significance due to the confirmed excessive inflammation in the severe cases of COVID-19. It is worth mentioning here that testing of the described therapeutics in COVID-19 clinical trials is based on either initial clinical observations or reported activity against previous outbreaks of SARS-CoV and MERS-CoV.
Lastly, although the individual use of the described therapeutics can be beneficial, yet a combination of the above drugs with each other and/or with those that impact the early stage of the viral life cycle will likely lead to a higher success rate in treating the critically ill patients. The clinical outcome is likely to be further improved by the addition of immune-therapeutics and anticoagulants to address the issues of cytokine storm and coagulopathies, respectively. Based on initial results, remdesivir, favipiravir, EIDD-2801, and selinexor appear to carry the most promising therapeutic effects. In fact, on May 1, 2020, the U.S. FDA issued an emergency use authorization for remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID-19 [25]. On May 30, 2020, the Russian Health Ministry approved a generic version of favipiravir named avifavir for the treatment of COVID-19 in the hospital settings [10].