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With the continual evolution of new strains of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that are more virulent, transmissible, and able to evade current vaccines, there is an urgent need for effective anti-viral drugs. The SARS-CoV-2 main protease (M pro ) is a leading target for drug design due to its conserved and indispensable role in the viral life cycle. Drugs targeting M pro  appear promising but will elicit selection pressure for resistance. To understand resistance potential in M pro , we performed a comprehensive mutational scan of the protease that analyzed the function of all possible single amino acid changes. We developed three separate high throughput assays of M pro  function in yeast, based on either the ability of M pro  variants to cleave at a defined cut-site or on the toxicity of their expression to yeast. We used deep sequencing to quantify the functional effects of each variant in each screen. The protein fitness landscapes from all three screens were strongly correlated, indicating that they captured the biophysical properties critical to M pro  function. The fitness landscapes revealed a non-active site location on the surface that is extremely sensitive to mutation, making it a favorable location to target with inhibitors. In addition, we found a network of critical amino acids that physically bridge the two active sites of the M pro  dimer. The clinical variants of M pro  were predominantly functional in our screens, indicating that M pro  is under strong selection pressure in the human population. Our results provide predictions of mutations that will be readily accessible to M pro  evolution and that are likely to contribute to drug resistance. This complete mutational guide of M pro  can be used in the design of inhibitors with reduced potential of evolving viral resistance.

Comprehensive fitness landscape of SARS-CoV-2 M pro reveals insights into viral resistance mechanisms