Computational design of ultrashort peptide inhibitors of the receptor-binding domain of the SARS-CoV-2 S protein

被引:25
|
作者
Pei, Pengfei [1 ]
Qin, Hongbo [1 ]
Chen, Jialin [1 ]
Wang, Fengli [1 ]
He, Chengzhi [2 ]
He, Shiting [1 ]
Hong, Bixia [1 ]
Liu, Ke [1 ]
Qiao, Renzhong [1 ]
Fan, Huahao [1 ,3 ]
Tong, Yigang [1 ,3 ]
Chen, Long [1 ]
Luo, Shi-Zhong [1 ]
机构
[1] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing 100029, Peoples R China
[2] Beijing Adv Innovat Ctr Soft Matter Sci & Engn, Beijing, Peoples R China
[3] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing Adv Innovat Ctr Soft Matter Sci & Engn, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
SARS-CoV-2; peptide inhibitor; computer-aided design; molecular dynamics simulation; COVID-19; FREE-ENERGY CALCULATIONS; CONTINUUM SOLVENT; MOLECULAR-MECHANICS; SPIKE PROTEIN; SURFACE-AREA; CORONAVIRUS; ELECTROSTATICS; STABILITY; DYNAMICS; GROMACS;
D O I
10.1093/bib/bbab243
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Targeting the interaction between severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)-receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) is believed to be an effective strategy for drug design to inhibit the infection of SARS-CoV-2. Herein, several ultrashort peptidase inhibitors against the RBD-ACE2 interaction were obtained by a computer-aided approach based on the RBD-binding residues on the protease domain (PD) of ACE2. The designed peptides were tested on a model coronavirus GX_P2V, which has 92.2 and 86% amino acid identity to the SARS-CoV-2 spike protein and RBD, respectively. Molecular dynamics simulations and binding free energy analysis predicted a potential binding pocket on the RBD of the spike protein, and this was confirmed by the specifically designed peptides SI5 alpha and SI5 alpha-b. They have only seven residues, showing potent antiviral activity and low cytotoxicity. Enzyme-linked immunosorbent assay result also confirmed their inhibitory ability against the RBD-ACE2 interaction. The ultrashort peptides are promising precursor molecules for the drug development of Corona Virus Disease 2019, and the novel binding pocket on the RBD may be helpful for the design of RBD inhibitors or antibodies against SARS-CoV-2.
引用
收藏
页数:15
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