SARS-CoV-2 3CL-protease inhibitors derived from ML300:  investigation of P1 and replacements of the 1,2,3-benzotriazole

• Published in: Research square
• Main Authors: Hooper, Alice, Macdonald, Jonathan D, Reilly, Brenna, Maw, Joshua, Wirrick, Aidan P, Han, Sang Hoon, Lindsey, A Abigail, Rico, Emma G, Romigh, Todd, Goins, Christopher M, Wang, Nancy S, Stauffer, Shaun
• Format: Journal Article
• Language: English
• Published: United States 11.05.2023

Starting from compound (CCF0058981), a structure-based optimization of the P1 subsite was performed against the severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL ). Inhibitor and the compounds disclosed bind to 3CL using a non-covalent mode of action that utilize a His163 H-bond interaction in the S1 subpocket. In an effort to examine more structurally diverse P1 groups a number of azoles and heterocycles were designed. Several azole ring systems and replacements, including C-linked azoles, with similar or enhanced potency relative to were discovered ( , , and ) with demonstrated IC values less than 100 nM. In addition, pyridyl and isoquinoline P1 groups were successful as P1 replacements leading to 3-methyl pyridyl (IC = 85 nM) and isoquinoline (IC = 26 nM). High resolution X-ray crystal structures of these inhibitors were utilized to confirm binding orientation and guide optimization. These findings have implications towards antiviral development and preparedness to combat SARS-like zoonotic coronavirus outbreaks.