Design, Synthesis, and Biological Evaluation of Ultrashort β‐Peptoids as Inhibitors of SARS‐CoV‐2 3CL Protease

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), causative agent of coronavirus disease 2019 (COVID 19), remains a global health burden. The relative success of Paxlovid as the only FDA approved oral pill for COVID19 validates M pro as a viable antiviral target. Similarly, the limitations of nirmatrelvir, the active ingredient in Paxlovid with its peptide character, present an opportunity for further development of a new generation of oral therapeutics against SARS‐CoV‐2. In the current study, a novel class of ultrashort β‐peptoid nirmatrelvir‐mimetics, equipped with nitrile or alkyne warheads, were designed, synthesized, and screened for antiviral activity against SARS‐CoV‐2 M pro . Out of thirty (30) ultrashort α‐ and β‐peptoids studied, compound BJB24 , a novel β‐peptoid designed to mimic nirmatrelvir, was the most potent, with 98.36% inhibition at 200 µM and IC 50 of 7.9 µM. Based on the in vitro activity, very good calculated pharmacokinetic profile, and its distinct advantages as a β‐peptoid, BJB24 and similar ultrashort β‐peptoids warrant further investigation as a new class of antiviral agents.