key: cord-0884039-1fp2txwj
authors: Chia, C. S. Brian
title: Novel Nitrile Peptidomimetics for Treating COVID-19
date: 2022-02-03
journal: ACS Med Chem Lett
DOI: 10.1021/acsmedchemlett.2c00030
sha: 2956302f84f21d244bcb26fa8d7585808a74002f
doc_id: 884039
cord_uid: 1fp2txwj

COVID-19 is a highly infectious disease caused by the viral pathogen SARS-CoV-2, causing an estimated 5.4 million fatalities globally in 2 years since its emergence in December 2019. On December 22, 2021, the U.S. FDA granted Emergency Use Authorization for the oral viral main protease inhibitor, Nirmatrelvir, to treat patients with mild-to-moderate COVID-19. This patent review reveals the structure–activity relationship of key inhibitors described in the patent WO 2021/250648 A1.

Nirmatrelvir was designed to specifically target the SARS-CoV-2 main protease (Mpro), also known as 3 chymotrypsinlike protease (3CLpro). This viral protease plays a critical role in coronavirus polyprotein processing, cleaving the polyprotein in at least 11 places to yield functional viral proteins and enzymes required for its survival and propagation. It is a peptidomimetic, designed based on the natural 3CLpro polypeptide substrate recognition sequence: valine−leucine−glutamine. An electrophilic nitrile moiety was introduced at its C-terminus so that, after the drug binds into the 3CLpro active site, the nitrile can then subsequently react with 3CLpro's Cys145 thiol (−SH) moiety, forming a covalent bond and thereby inhibiting the viral protease.

The present patent application describes 98 novel coronavirus 3CLpro peptidomimetic inhibitors that can be used to inhibit viral replication and can potentially be used for treating COVID-19. It also includes methods of administering a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor to COVID-19 patients.

Key Structures. The inventors described 98 novel structures with their synthetic methods. Key exemplified structures and their biological activities are shown vide infra.

Biological Assay. SARS-CoV-2 3CLpro K i values were determined in a biochemical SARS-CoV-2 3CLpro fluorescence resonance energy transfer (FRET) competition assay where the exemplified compounds were challenged with a fluorogenic peptide substrate in the presence of SARS-CoV-2 3CLpro. EC 50 values were determined in a cell-based assay using VeroE6 cells enriched for hACE2 expression and tested using SARS-CoV-2. Cell viability was measured using CellTiter-Glo (Promega) to quantify cellular ATP levels.

Biological Data. The SARS-CoV-2 3CLpro K i and EC 50 data of key inhibitors are summarized in the following table.

Brian Chia − Experimental Drug Development Centre

Email: cschia@eddc.a-star

Complete contact information is available at: https://pubs.acs.org/10.1021/acsmedchemlett.2c00030

The author declares no competing financial interest.

The author thanks the Agency for Science, Technology and Research (ASTAR), Singapore, for funding this patent review.