Monitoring for SARS-CoV-2 drug resistance mutations in broad viral populations

Abstract

The search for drugs against COVID-19 and other diseases caused by coronaviruses focuses on the most conserved and essential proteins, mainly the main (Mpro) and the papain-like (PLpro) proteases and the RNA-dependent RNA polymerase (RdRp). Nirmatrelvir, an inhibitor for Mpro, was recently approved by FDA as a part of a two-drug combination, Paxlovid, and many more drugs are in various stages of development. Multiple candidates for the PLpro inhibitors are being studied, but none have yet progressed to clinical trials. Several repurposed inhibitors of RdRp are already in use. We can expect that once anti-COVID-19 drugs become widely used, resistant variants of SARS-CoV-2 will emerge, and we already see that for the drugs targeting SARS-CoV-2 RdRp. We hypothesize that emergence of such variants can be anticipated by identifying possible escape mutations already present in the existing populations of viruses. Our group previously developed the coronavirus3D server (https://coronavirus3d.org), tracking the evolution of SARS- CoV-2 in the context of the three-dimensional structures of its proteins. Here we introduce dedicated pages tracking the emergence of potential drug resistant mutations to Mpro and PLpro, showing that such mutations are already circulating in the SARS-CoV-2 viral population. With regular updates, the drug resistance tracker provides an easy way to monitor and potentially predict the emergence of drug resistance-conferring mutations in the SARS-CoV-2 virus.

SARS-CoV-2 evolution in the absence of selective immune pressures, results in antibody resistance, interferon suppression and phenotypic differences by lineage

“…Of the 41 variant alleles that arose de-novo or changed in frequency during the study, several are of clinical interest ( Figure 4, Table 1 ). A4981G, which arose de-novo and persisted in Beta lineage virus in P17 ( Figure 4 ), was predicted to possibly confer drug resistance to papain-like protease inhibitors (31), such as ritonavir used clinically in combination with nirmatrelvir that protects patients against severe COVID-19 (32, 33). C22674T, or spike S371F, which arose de-novo and persisted in two animals in P20 for Beta and P13 for Delta virus ( Figure 4 ), represents an Omicron-specific mutation arising in a study that did not use Omicron.…”

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

“…A major concern, however, is the potential for emergence of drugresistant SARS-CoV-2 mutants. Genomic surveillance of SARS-CoV-2 has been performed on a large scale since the beginning of the pandemic, enabling the detection of new alleles while they are still rare (24)(25)(26)(27)(28)(29)(30). This may guide the preemptive development of new drugs to address mutants that resist available treatments.…”

CMPK2 is a host restriction factor that inhibits infection of multiple coronaviruses in a cell-intrinsic manner

“…Although RdRp is an obvious target of antiviral therapeutics development, Gilead’s remdesivir and Merck’s molnupiravir represent the only 2 FDA-authorized antiviral drugs [ 9 , 10 ]. In addition, there is significant concern that monotherapy would rapidly result in the emergence of resistance [ 11 , 12 ].…”