BJB24 for COVID-19

AbstractThe 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 Mpro 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 Mpro. 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 IC50 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.