AUTHOR=Yin Shengnan , Mei Shuang , Li Zhiqin , Xu Zhen , Wu Yuting , Chen Xiujuan , Liu Dongmei , Niu Miao-Miao , Li Jindong 

TITLE=Non-covalent cyclic peptides simultaneously targeting Mpro and NRP1 are highly effective against Omicron BA.2.75

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1037993

DOI=10.3389/fphar.2022.1037993

ISSN=1663-9812

ABSTRACT=<p>Available vaccine-based immunity may at high risk of being evaded due to substantial mutations in the variant Omicron. The main protease (Mpro) of SARS-CoV-2 and human neuropilin-1 (NRP1), two less mutable proteins, have been reported to be crucial for SARS-CoV-2 replication and entry into host cells, respectively. Their dual blockade may avoid vaccine failure caused by continuous mutations of the SARS-CoV-2 genome and exert synergistic antiviral efficacy. Herein, four cyclic peptides non-covalently targeting both Mpro and NRP1 were identified using virtual screening. Among them, MN-2 showed highly potent affinity to Mpro (<italic>K</italic><sub>d</sub> = 18.2 ± 1.9 nM) and NRP1 (<italic>K</italic><sub>d</sub> = 12.3 ± 1.2 nM), which was about 3,478-fold and 74-fold stronger than that of the positive inhibitors Peptide-21 and EG3287. Furthermore, MN-2 exhibited significant inhibitory activity against Mpro and remarkable anti-infective activity against the pseudotyped variant Omicron BA.2.75 without obvious cytotoxicity. These data demonstrated that MN-2, a novel non-covalent cyclic peptide, is a promising agent against Omicron BA.2.75.</p>