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

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São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil
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Department of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil
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Department of Genetics and Evolution, Federal University of São Carlos, Rodovia Washington Luís km 235, São Carlos 13565-905, SP, Brazil
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The Sao Paulo School of Medicine, Federal University of São Paulo, Rua Três de Maio, 100, São Paulo 04044-020, SP, Brazil
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Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo 05508-900, SP, Brazil
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Department of Pharmaceutical Sciences, Federal University of São Paulo, Rua São Nicolau, 210, Diadema 09913-030, SP, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editors: Jean-Marc Sabatier and Simona Rapposelli
Molecules 2021, 26(16), 4896; https://doi.org/10.3390/molecules26164896
Received: 26 March 2021 / Revised: 5 August 2021 / Accepted: 7 August 2021 / Published: 12 August 2021
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28–65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0–3.5 µM) and binding affinities (Kd = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). 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. View Full-Text
Keywords: COVID-19; SARS-CoV-2; inhibitors; Papain-like protease; peptides COVID-19; SARS-CoV-2; inhibitors; Papain-like protease; peptides
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MDPI and ACS Style

Freire, M.C.L.C.; Noske, G.D.; Bitencourt, N.V.; Sanches, P.R.S.; Santos-Filho, N.A.; Gawriljuk, V.O.; de Souza, E.P.; Nogueira, V.H.R.; de Godoy, M.O.; Nakamura, A.M.; Fernandes, R.S.; Godoy, A.S.; Juliano, M.A.; Peres, B.M.; Barbosa, C.G.; Moraes, C.B.; Freitas-Junior, L.H.G.; Cilli, E.M.; Guido, R.V.C.; Oliva, G. Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors. Molecules 2021, 26, 4896. https://doi.org/10.3390/molecules26164896

AMA Style

Freire MCLC, Noske GD, Bitencourt NV, Sanches PRS, Santos-Filho NA, Gawriljuk VO, de Souza EP, Nogueira VHR, de Godoy MO, Nakamura AM, Fernandes RS, Godoy AS, Juliano MA, Peres BM, Barbosa CG, Moraes CB, Freitas-Junior LHG, Cilli EM, Guido RVC, Oliva G. Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors. Molecules. 2021; 26(16):4896. https://doi.org/10.3390/molecules26164896

Chicago/Turabian Style

Freire, Marjorie C.L.C., Gabriela D. Noske, Natália V. Bitencourt, Paulo R.S. Sanches, Norival A. Santos-Filho, Victor O. Gawriljuk, Eduardo P. de Souza, Victor H.R. Nogueira, Mariana O. de Godoy, Aline M. Nakamura, Rafaela S. Fernandes, Andre S. Godoy, Maria A. Juliano, Bianca M. Peres, Cecília G. Barbosa, Carolina B. Moraes, Lucio H.G. Freitas-Junior, Eduardo M. Cilli, Rafael V.C. Guido, and Glaucius Oliva. 2021. "Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors" Molecules 26, no. 16: 4896. https://doi.org/10.3390/molecules26164896

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