Abstract
The SARS‐CoV‐2 main protease (Mpro) has a pivotal role in mediating viral genome replication and transcription of the coronavirus, making it a promising target for drugs against the COVID‐19 pandemic. Here, a crystal structure is presented in which Mpro adopts an inactive state that has never been observed before, called new‐inactive. It is shown that the oxyanion loop, which is involved in substrate recognition and enzymatic activity, adopts a new catalytically incompetent conformation and that many of the key interactions of the active conformation of the enzyme around the active site are lost. Solvation/desolvation energetic contributions play an important role in the transition from the inactive to the active state, with Phe140 moving from an exposed to a buried environment and Asn142 moving from a buried environment to an exposed environment. In new‐inactive Mpro a new cavity is present near the S2′ subsite, and the N‐terminal and C‐terminal tails, as well as the dimeric interface, are perturbed, with partial destabilization of the dimeric assembly. This novel conformation is relevant both for comprehension of the mechanism of action of Mpro within the catalytic cycle and for the successful structure‐based drug design of antiviral drugs.
Highlights
To face the global COVID-19 pandemic, besides prevention via the use of vaccines, it is essential to develop targeted therapeutic options for patients infected by the SARS-CoV-2 betacoronavirus
As ‘positive’ controls, we considered ligand-free main protease (Mpro) and Mpro in complex with the known -ketoamide covalent reversible inhibitor boceprevir, an approved HCV drug that is able to bind to SARS-CoV-2 Mpro (Fu et al, 2020)
There were a significant number of cases, around ten, in which the electron density was of much lower quality or was even absent in particular portions of the protein, namely residues 139–144 of the oxyanion loop, residues 1–3 of the N-finger and the side chain of His163 in the S1 specificity subsite, all of which are
Summary
To face the global COVID-19 pandemic, besides prevention via the use of vaccines, it is essential to develop targeted therapeutic options for patients infected by the SARS-CoV-2 betacoronavirus. One of the most promising classes of antiviral drug candidates are protease inhibitors, small molecules that are able to inhibit enzymes involved in virus replication within the cell. The main protease, Mpro, is a cysteine peptidase that is essential for the replication cycle of positivesense, single-stranded RNA coronaviruses (Xia & Kang, 2011), including SARS-CoV-2. It is known as 3C-like protease or 3CLpro from the similarity of its active site and its substrate specificity to those of the picornavirus 3C protease (Anand et al, 2002). There are at least two SARS-CoV-2 Mpro inhibitors in phase I clinical trials as candidates with potent antiviral activity: the orally administered PF-07321332 (Pavan et al, 2021) and the intravenously administered PF-00835231 (Ahmad et al, 2021)
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