Kill or corrupt: Mechanisms of action and drug-resistance of nucleotide analogues against SARS-CoV-2.

Nucleoside/tide analogues (NAs) have long been used in the fight against viral diseases, and now present a promising option for the treatment of COVID-19. Once activated to the 5'-triphosphate state, NAs act by targeting the viral RNA-dependent RNA-polymerase for incorporation into the viral RNA genome. Incorporated analogues can either 'kill' (terminate) synthesis, or 'corrupt' (genetically or chemically) the RNA. Against coronaviruses, the use of NAs has been further complicated by the presence of a virally encoded exonuclease domain (nsp14) with proofreading and repair capacities. Here, we describe the mechanism of action of four promising anti-COVID-19 NAs; remdesivir, molnupiravir, favipiravir and bemnifosbuvir. Their distinct mechanisms of action best exemplify the concept of 'killers' and 'corruptors'. We review available data regarding their ability to be incorporated and excised, and discuss the specific structural features that dictate their overall potency, toxicity, and mutagenic potential. This should guide the synthesis of novel analogues, lend insight into the potential for resistance mutations, and provide a rational basis for upcoming combinations therapies.