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.

Keywords: Animal model; COVID-19; Carboxylesterases; Coronavirus; Drug-drug interactions, interspecies difference; Pandemic; Remdesivir; SARS-CoV-2.

Fig. 1

Chemical structure of remdesivir, sofosbuvir, tenofovir disoproxil and tenofovir alafenamide Those are nucleoside/nucleotide drugs featured by the heterocyclic ring linked to the phosphorus atom at the center. The connecting atoms are pointed by a red arrow

Fig. 2

Therapeutic activation of remdesivir. This antiviral agent undergoes hydrolysis followed by several phosphorylation steps to form the antiviral metabolite nucleoside triphosphate. In human, the hydrolysis is achieved by CES1 but enzyme(s) for phosphorylation remains to be determined

Fig. 3

Diagrammatic presentation of carboxylesterases-based drug interactions with remdesivir. This virial agent is a substrate of CES1 but an irreversible inhibitor of CES2. Therefore, remdesivir catalytically impacts both enzymes (solid lines). In addition, many drugs and other xenobiotic compounds as well as disease mediators such as cytokines are established to regulate the expression of both enzymes. It is assumed that remdesivir has a potential of interacting with those factors (dotted lines)

Fig. 4

Immunoblots of liver microsomes and serum from various species with anti-rat Ces1d. Microsomes (10 μg) or serum (0.5 μL) from mature males were resolved by 7.5% SDS-PAGE and transferred electrophoretically to nitrocellulose membranes. The blots were blocked by milk and detected by the antibody against recombinant rat Ces1d through E. coli expression system. This antibody has been shown to have a broad-cross reactivity activity among carboxylesterases