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Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors.
Freire, Marjorie C L C; Noske, Gabriela D; Bitencourt, Natália V; Sanches, Paulo R S; Santos-Filho, Norival A; Gawriljuk, Victor O; de Souza, Eduardo P; Nogueira, Victor H R; de Godoy, Mariana O; Nakamura, Aline M; Fernandes, Rafaela S; Godoy, Andre S; Juliano, Maria A; Peres, Bianca M; Barbosa, Cecília G; Moraes, Carolina B; Freitas-Junior, Lucio H G; Cilli, Eduardo M; Guido, Rafael V C; Oliva, Glaucius.
  • Freire MCLC; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • Noske GD; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • Bitencourt NV; Department of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil.
  • Sanches PRS; Department of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil.
  • Santos-Filho NA; Department of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil.
  • Gawriljuk VO; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • de Souza EP; Department of Genetics and Evolution, Federal University of São Carlos, Rodovia Washington Luís km 235, São Carlos 13565-905, SP, Brazil.
  • Nogueira VHR; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • de Godoy MO; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • Nakamura AM; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • Fernandes RS; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • Godoy AS; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • Juliano MA; The Sao Paulo School of Medicine, Federal University of São Paulo, Rua Três de Maio, 100, São Paulo 04044-020, SP, Brazil.
  • Peres BM; Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo 05508-900, SP, Brazil.
  • Barbosa CG; Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo 05508-900, SP, Brazil.
  • Moraes CB; Department of Pharmaceutical Sciences, Federal University of São Paulo, Rua São Nicolau, 210, Diadema 09913-030, SP, Brazil.
  • Freitas-Junior LHG; Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo 05508-900, SP, Brazil.
  • Cilli EM; Department of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil.
  • Guido RVC; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
  • Oliva G; São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, Brazil.
Molecules ; 26(16)2021 Aug 12.
Article in English | MEDLINE | ID: covidwho-1355016
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptides / Papain / Dimerization / Crotalid Venoms / SARS-CoV-2 Type of study: Prognostic study Language: English Journal subject: Biology Year: 2021 Document Type: Article Affiliation country: Molecules26164896

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptides / Papain / Dimerization / Crotalid Venoms / SARS-CoV-2 Type of study: Prognostic study Language: English Journal subject: Biology Year: 2021 Document Type: Article Affiliation country: Molecules26164896