Fig. 1. Molnupiravir induces mutations by acting as a nucleotide analogue with multiple tautomeric forms that pair preferentially with different nucleotides.

a, Molnupiravir triphosphate can assume multiple tautomeric forms that resemble different nucleotides. The N-hydroxylamine form resembles cytosine (C); like cytosine, it can pair with guanine (G) while the oxime form more closely resembles uracil (U) and thus can pair with adenine (A) (figure adapted in part from Malone and Campbell⁴⁵). b, In the most common scenario, molnupiravir (M) is incorporated in the N-hydroxylamine form opposite a G nucleotide. It can then tautomerize into the oxime form, which can then pair to an A in subsequent replication, creating a G-to-A mutation. c, Molnupiravir can result in four different mutation types. In the first column, a G-to-A mutation is created by M incorporation opposite a positive-sense G, which can then pair with an A in the next positive-sense synthesis. In the second column, the positive-sense genome contains a C, which results in a G in the negative-sense genome. This G can then undergo the same G-to-A mutation, creating a negative-sense A that finally results in a U in the positive-sense genome, meaning that the entire process results in a C-to-U mutation. Although the biases of tautomeric forms for the free and incorporated MTP nucleotides favour this directionality of mutations, with M incorporated in the N-hydroxylamine form and then transitioning to the oxime form, the reverse can also occur: this results in A-to-G and U-to-C mutations.