Nicotine-Inspired, De Novo-Designed SARS-CoV-2 Main Protease Inhibitors Reveal Unique Chemistry for Covalently...

Area of Science:

• Medicinal Chemistry
• Virology
• Structural Biology

Background:

• Anecdotal observations suggested lower SARS-CoV-2 infection rates in smokers.
• This prompted investigation into nicotine and its derivatives as potential SARS-CoV-2 main protease (M^Pro) inhibitors.

Purpose of the Study:

• To identify novel covalent inhibitors of SARS-CoV-2 M^Pro.
• To explore the structure-activity relationships of a new class of M^Pro inhibitors based on a dichloroacetamide scaffold.

Main Methods:

• De novo design of covalent inhibitors starting from 3-vinylpyridine, a weak M^Pro binder.
• Structure determination of eight M^Pro-inhibitor complexes using X-ray crystallography.
• Biochemical assays to determine inhibitory concentrations (IC₅₀).

Main Results:

• Discovery of SR-A-174, a potent M^Pro inhibitor with an IC₅₀ of 60 nM.
• Identification of multiple potent covalent M^Pro inhibitors featuring an N,N-diaryl-α,α-dichloroacetamide scaffold.
• Observed novel dual covalent modification of the M^Pro catalytic dyad (Cys145 and His41) by two inhibitors.

Conclusions:

• The N,N-diaryl-α,α-dichloroacetamide scaffold represents a novel class of M^Pro inhibitors.
• The dual covalent modification mode offers a new strategy for targeting viral proteases.
• This reactivity may enable novel bioconjugation approaches for cysteine and histidine residues.