Antiviral nucleoside mimics: the development and future perspective of Molnupiravir

In 2021, the U.S. Food and Drug Administration (FDA) authorized the oral prodrug molnupiravir, the β-D-N4-hydroxycytidine precursor, for emergency use as an antiviral agent against SARS-CoV-2. Molnupiravir (MK-4482, EIDD-2801) was originally developed at Emory University, where its design leveraged the bioisosteric replacement of the carbonyl group in the pyrimidine base of endogenous uridine with an oxime (NHOH) functionality. This modification enabled effective mimicking of natural nucleosides and enhanced antiviral activity by targeting the viral RNA-dependent RNA polymerase (RdRp). In this review, the collective advancements in the synthesis of molnupiravir aimed at achieving scalable, cost-effective, and efficient manufacturing are discussed, along with an exploration of oxime bioisosterism within medicinal chemistry.