Structure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease

Abstract

There is a clinical need for direct-acting antivirals targeting SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, to complement current therapeutic strategies. The main protease (M pro ) is an attractive target for antiviral therapy. However, the vast majority of protease inhibitors described thus far are peptidomimetic and bind to the active-site cysteine via a covalent adduct, which is generally pharmacokinetically unfavorable. We have reported the optimization of an existing FDA-approved chemical scaffold, perampanel, to bind to and inhibit M pro noncovalently with IC 50 s in the low-nanomolar range and EC 50 s in the low-micromolar range. Here, we present nine crystal structures of M pro bound to a series of perampanel analogs, providing detailed structural insights into their mechanism of action and structure-activity relationship. These insights further reveal strategies for pursuing rational inhibitor design efforts in the context of considerable active-site flexibility and potential resistance mechanisms.

Quercetin and Luteolin Are Single-digit Micromolar Inhibitors of the SARS-CoV-2 RNA-dependent RNA Polymerase

“…These computational insights will serve to start future campaigns for hit-to-lead design, as witnessed recently in computational studies used to guide experiments for drug design targeting viral proteins. [49,50] Notably, Jorgensen et al [51] recently performed a virtual screening of ∼2000 approved drugs with a consensus virtual screening protocol used together with MD simulations and biochemical assay. This indicated 14 known drugs active in the micromolar range against 3CL pro .…”

Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2

“…These structures also indicate that the P2′ to P4′ sites demonstrate a higher conformational diversity than those for the P6 to P1′ sites, due to the lack of protease substrate specificity at these positions. We compared several published M pro –inhibitor complex structures ( 15 , 16 , 18 , 19 , 21 , 32 – 34 ) with the structure of M pro in complex with nsp4|5, which has the strongest binding affinity to M pro among the substrates we tested ( SI Appendix , Fig. S8 ).…”

Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds

“…Moreover, compound 5 provided evidence of synergy with remdesivir. In terms of interactions with the active site, compound 5 was shown to form three hydrogen bonds with active site residues Gly143, His163 and Met165, whereas the detailed interactions of compound 26 are not described [15] , [53] .…”