A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

Abstract

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.

SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

“…Another approach of enhanced antiviral combat considers alternative warhead chemistries to increase target specificity as well as drug bioavailability and clearance after successful therapy. An example that explores the chemical space around the reactive electrophilic warhead shows promising potential to finetune inhibitor properties to desired parameters solely by exchange of the reactive head group [116]. Aside from the already employed diversity of functional groups, novel chemistries that have the potential to improve target interaction can be derived from wider drug repurposing screens, including, for example, boronic acids, such as in ixazomib [117].…”

Advanced approaches of developing targeted covalent drugs

“…Nirmatrelvir analogues with different warheads and their inhibitory activities were also investigated, suggesting that hydroxymethylketone and ketobenzothiazole warheads can also be employed for treating coronavirus infections equipotent to the nitrile. 58 To clearly characterise differences between structures and biochemical activities, herein we exhibit the structures and cellular/enzymatic IC 50 values of all drugs mentioned above (Table 1).…”

“…Nirmatrelvir analogues with different warheads and their inhibitory activities were also investigated, suggesting that hydroxymethylketone and ketobenzothiazole warheads can also be employed for treating coronavirus infections equipotent to the nitrile. 58…”

SARS‐CoV‐2 main protease inhibitors: What is moving in the field of peptides and peptidomimetics?

“…This complex helps in explaining the inhibitory mechanism of nirmaltrevir, as a reversible covalent inhibitor, in which the nitrile warhead joints covalently with the Cys145 side-chain thiol group (Fig. 2), the conformationally restricted Gln and Pro residues occupy the S1 and S2 subsites, respectively, Modification of the nitrile covalent warhead of nirmaltrevir indicated that an aldehyde, a hydroxymethylketone and a ketobenzothiazole group provided potent inhibitors in the isolated enzyme assays, while other less electrophilic groups led to inactive compound [31] .…”