| Autor: |
Geng ZZ, Atla S, Shaabani N, Vulupala VR, Yang KS, Alugubelli YR, Khatua K, Chen PC, Xiao J, Blankenship LR, Ma XR, Vatansever EC, Cho CC, Ma Y, Allen R, Ji H, Xu S, Liu WR |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 18. Date of Electronic Publication: 2023 Jan 18. |
| DOI: |
10.1101/2023.01.17.524469 |
| Abstrakt: |
SARS-CoV-2 is the coronavirus pathogen of the currently prevailing COVID-19 pandemic. It relies on its main protease (M Pro ) for replication and pathogenesis. M Pro is a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as M Pro inhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 reversibly covalent dipeptidyl M Pro inhibitors and characterized them on in vitro enzymatic inhibition potency, structures of their complexes with M Pro , cellular M Pro inhibition potency, antiviral potency, cytotoxicity, and in vitro metabolic stability. Our results indicated that M Pro has a flexible S2 pocket that accommodates dipeptidyl inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as ( S )-2-azaspiro[4,4]nonane-3-carboxylate and ( S )-2-azaspiro[4,5]decane-3-carboxylate have optimal characteristics. One compound MPI60 containing a P2 ( S )-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and high in vitro metabolic stability and can be potentially advanced to further preclinical tests. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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