The nucleoside antiviral prodrug remdesivir in treating COVID-19 and beyond with interspecies significance

Abstract

Infectious pandemics result in hundreds and millions of deaths, notable examples of the Spanish Flu, the Black Death and smallpox. The current pandemic, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is unprecedented even in the historical term of pandemics. The unprecedentedness is featured by multiple surges, rapid identification of therapeutic options and accelerated development of vaccines. Remdesivir, originally developed for Ebola viral disease, is the first treatment of COVID-19 (Coronavirus disease 2019) approved by the United States Food and Drug Administration. As demonstrated by in vitro and preclinical studies, this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species. However, randomized controlled trials have failed to confirm the efficacy and safety. Remdesivir improves some clinical signs but not critical parameters such as mortality. This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity. Remdesivir is given intravenously, leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity. This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.

Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

“…Compared with the placebo, the molnupiravir group has a higher incidence of bacterial pneumonia, nausea, and dizziness, 70 and the nirmatrelvir group has a higher incidence of dysgeusia, diarrhea, elevated alanine aminotransferase, headache, creatinine clearance, nausea, and vomiting 71 . The remdesivir groups from multiple clinical trials have a wide range of serious adverse events from cardiovascular events, to pulmonary disorders, and to hepatic dysfunction 36,78–82 …”

“…For example, molnupiravir has been shown to potently inhibit the replication of influenza virus, a member of the family Orthomyxoviridae 91 . Likewise, members of the family Filoviridae are highly sensitive toward remdesivir with an EC 50 value of as low as 3 nM, 10 or more times of the sensitivity of SARS‐CoV‐2, a member of the family Coronaviridae 36,86 …”

“…Molnupiravir, nirmatrelvir, and remdesivir undergo extensive metabolism, 36,92–99 primarily through hydrolysis, oxidation, or both (Table 4). All three drugs undergo hydrolysis, whereas nirmatrelvir and remdesivir also undergo oxidation.…”

“…NHC, the hydrolytic metabolite of molnupiravir, undergoes three‐step phosphorylation to produce monophosphate, diphosphate, and ultimately triphosphate, respectively. Potent antiviral activity is mainly driven by the triphosphate metabolite 36,105 . The identities of kinases for the phosphorylation remain to be determined.…”

“…The combination was authorized in December of 2021 for the treatment of mild and moderate COVID‐19 in adults and children 12 or older. The Spike protein, on the other hand, is extensively glycosylated, undergoes conformational changes, and exhibits great potential for rapid mutations 34–36 . These characteristics are linked to waning immunity against COVID‐19, as shown by breakthrough infection and multiple surges 37–39 …”