Peptide Aldehydes\nIncorporating Thiazol-4-yl Alanine Are Potent In Vitro Inhibitors\nof SARS-CoV‑2 Main Protease

The main protease of SARS-CoV-2 is\nan essential enzyme required\nfor polyprotein cleavage during viral replication and thus is an excellent\ntarget for development of direct-acting antiviral compounds. Continued\nresearch efforts have elucidated several peptidic small molecules\nlike GC376, boceprevir, and nirmatrelvir with potent anticoronaviral\nactivity bearing optimized amino acid side chain residues. To reduce\nsynthetic complexity and cost, we used simple chemical surrogates\nthat were commercially readily available to develop new inhibitors\nthat mimic the potency of these drug compounds. We synthesized and\ntested several analogue chimeras of GC376 and boceprevir that have\nsurrogate residues at the P1 and/or P2 position in order to further\nimprove target binding. Both P1 variants with either a nonpolar cyclobutyl\nor polar thiazol-4-yl alanine resulted in low-micromolar to submicromolar\nM<sup>pro</sup> inhibitors with strong antiviral activity in cell\nassays.