Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors

被引:23
作者
Freire, Marjorie C. L. C. [1 ]
Noske, Gabriela D. [1 ]
Bitencourt, Natalia V. [2 ]
Sanches, Paulo R. S. [2 ]
Santos-Filho, Norival A. [2 ]
Gawriljuk, Victor O. [1 ]
de Souza, Eduardo P. [3 ]
Nogueira, Victor H. R. [1 ]
de Godoy, Mariana O. [1 ]
Nakamura, Aline M. [1 ]
Fernandes, Rafaela S. [1 ]
Godoy, Andre S. [1 ]
Juliano, Maria A. [4 ]
Peres, Bianca M. [5 ]
Barbosa, Cecilia G. [5 ]
Moraes, Carolina B. [6 ]
Freitas-Junior, Lucio H. G. [5 ]
Cilli, Eduardo M. [2 ]
Guido, Rafael V. C. [1 ]
Oliva, Glaucius [1 ]
机构
[1] Univ Sao Paulo, Sao Carlos Inst Phys, Ave Joao Dagnone 1100, BR-13563120 Sao Carlos, SP, Brazil
[2] Sao Paulo State Univ UNESP, Inst Chem, Dept Biochem & Organ Chem, BR-14800060 Araraquara, SP, Brazil
[3] Univ Fed Sao Carlos, Dept Genet & Evolut, Rodovia Washington Luis Km 235, BR-13565905 Sao Carlos, SP, Brazil
[4] Univ Fed Sao Paulo, Sao Paulo Sch Med, Rua Tres Maio 100, BR-04044020 Sao Paulo, SP, Brazil
[5] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Av Prof Lineu Prestes 1374, BR-05508900 Sao Paulo, SP, Brazil
[6] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Rua Sao Nicolau 210, BR-09913030 Diadema, SP, Brazil
基金
巴西圣保罗研究基金会;
关键词
COVID-19; SARS-CoV-2; inhibitors; Papain-like protease; peptides; SYNTHETIC PEPTIDES; SPIKE PROTEIN; SARS-COV; COOPERATIVITY; REGIONS; BINDING; FUSION;
D O I
10.3390/molecules26164896
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys(11), Lys(12),Lys(13)-(pBthTX-I)(2)K ((pBthTX-I)(2)K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)(2)K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28-65 mu M) and mostly low cytotoxic effect (CC50 > 100 mu M). To shed light on the mechanism of action underlying the peptides' antiviral activity, the Main Protease (M-pro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC(50)s = 1.0-3.5 mu M) and binding affinities (K-d = 0.9-7 mu M) at the low micromolar range but poor inhibitory activity against M-pro (IC50 > 10 mu M). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.
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页数:17
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