A multi-pronged evaluation of aldehyde-based tripeptidyl main protease inhibitors as SARS-CoV-2 antivirals

Potent and biostable inhibitors of the main protease of SARS-CoV-2

“… 20 In addition, several other M pro inhibitors have been developed to date. 21 , 22 , 23 , 24 , 25 , 26 , 27 As the development of additional several drugs is required for a repertory of drug choice, we have tried to develop other M pro inhibitors. Previously, we characterized a hit compound, 5h ( 2 ), as a SARS-CoV-2 M pro inhibitor 19 among a panel of known compounds, which had originally shown inhibitory activity against SARS-CoV ( Figure 1 ).…”

A Novel Y-Shaped, S–O–N–O–S-Bridged Cross-Link between Three Residues C22, C44, and K61 Is Frequently Observed in the SARS-CoV-2 Main Protease

“…This region is part of the M Pro active site, serving as a cap of the protein S2 site to bind the P2 residue in a peptide substrate (Figure 1A). 26,30,31 The electron density of this region was very weak in all of the determined M Pro −inhibitor structures, indicating a highly flexible conformation (Figures 1B and S4). There have been many other M Pro −inhibitor complexes whose crystal structures have been determined and deposited into the Protein Data Bank.…”

“…This relatively open form of M Pro is considered more desirable than a closed form in representing M Pro in solution as well since M Pro dimers in solution are not expected to interact with each other. Therefore, we have soaked these apo M Pro crystals with different inhibitors for the determination of crystal structures of more than 30 M Pro –inhibitor complexes. ,, One unique observation that we have made for almost all of our determined M Pro –inhibitor structures is a poorly defined conformation for the aa46–50 region. This region is part of the M Pro active site, serving as a cap of the protein S2 site to bind the P2 residue in a peptide substrate (Figure A). ,, The electron density of this region was very weak in all of the determined M Pro –inhibitor structures, indicating a highly flexible conformation (Figures B and S4).…”

SARS‐CoV‐2 main protease inhibitors: What is moving in the field of peptides and peptidomimetics?

“…The same group prepared a series of di-and tripeptide derivatives with an aldehyde as the warhead moiety, and the conformationally restricted -lactam Gln mimetic at P1 position, which revealed as compounds with potent inhibitory activity in the isolated SARS-CoV-2 Mpro, and a few examples with submicromolar antiviral activity in cell cultures infected with 10991387, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/psc.3467 by Csic Organización Central Om (Oficialia Mayor) (Urici), Wiley Online Library on [12/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License different SARS-CoV-2 strains [33] . The 16 solved structures of peptidomimetic inhibitor-Mpro complexes showed covalent binding through the aldehyde (hemithioacetal), various Hbond, especially with the P1 -lactam, and profuse, hydrophobic van der Waals interactions with P2 and P3 side-chains.…”

“…The same group prepared a series of dipeptide and tripeptide derivatives with an aldehyde as the warhead moiety and the conformationally restricted γ‐lactam Gln mimetic at P1 position, which revealed as compounds with potent inhibitory activity in the isolated SARS‐CoV‐2 Mpro, and a few examples displayed submicromolar antiviral activity in cell cultures infected with different SARS‐CoV‐2 strains. 33 The 16 solved structures of peptidomimetic inhibitor Mpro complexes showed covalent binding through the aldehyde (hemithioacetal), various H bond, especially with the P1 γ‐lactam, and profuse, hydrophobic van der Waals interactions with P2 and P3 side chains. Furthermore, in another paper, 34 this group described that these dipeptide and tripeptide aldehydes highly inhibited isolated cathepsin L, B, and K host enzymes.…”