Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors
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...
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MDPI AG
2021-08-01
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| author | Marjorie C. L. C. Freire 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 Glaucius Oliva |
| author_facet | Marjorie C. L. C. Freire 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 Glaucius Oliva |
| author_sort | Marjorie C. L. C. Freire |
| collection | DOAJ |
| description | 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<sup>11</sup>, Lys<sup>12</sup>,Lys<sup>13</sup>-(pBthTX-I)<sub>2</sub>K (<b>(pBthTX-I)<sub>2</sub>K)</b>) and derivatives against SARS-CoV-2 are reported. The lead peptide <b>(pBthTX-I)<sub>2</sub>K</b> and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC<sub>50</sub> = 28–65 µM) and mostly low cytotoxic effect (CC<sub>50</sub> > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (M<sup>pro</sup>) and Papain-Like protease (PL<sup>pro</sup>) inhibitory activities of the peptides were assessed. The synthetic peptides showed PL<sup>pro</sup> inhibition potencies (IC<sub>50</sub>s = 1.0–3.5 µM) and binding affinities (<i>K</i><sub>d</sub> = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against M<sup>pro</sup> (IC<sub>50</sub> > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PL<sup>pro</sup> 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. |
| first_indexed | 2024-03-10T08:33:23Z |
| format | Article |
| id | doaj.art-9de96259efb449498e199a11622b3e44 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T08:33:23Z |
| publishDate | 2021-08-01 |
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| series | Molecules |
| spelling | doaj.art-9de96259efb449498e199a11622b3e442023-11-22T08:53:35ZengMDPI AGMolecules1420-30492021-08-012616489610.3390/molecules26164896Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease InhibitorsMarjorie C. L. C. Freire0Gabriela D. Noske1Natália V. Bitencourt2Paulo R. S. Sanches3Norival A. Santos-Filho4Victor O. Gawriljuk5Eduardo P. de Souza6Victor H. R. Nogueira7Mariana O. de Godoy8Aline M. Nakamura9Rafaela S. Fernandes10Andre S. Godoy11Maria A. Juliano12Bianca M. Peres13Cecília G. Barbosa14Carolina B. Moraes15Lucio H. G. Freitas-Junior16Eduardo M. Cilli17Rafael V. C. Guido18Glaucius Oliva19São Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilDepartment of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, BrazilDepartment of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, BrazilDepartment of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilDepartment of Genetics and Evolution, Federal University of São Carlos, Rodovia Washington Luís km 235, São Carlos 13565-905, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilThe Sao Paulo School of Medicine, Federal University of São Paulo, Rua Três de Maio, 100, São Paulo 04044-020, SP, BrazilDepartment of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo 05508-900, SP, BrazilDepartment of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo 05508-900, SP, BrazilDepartment of Pharmaceutical Sciences, Federal University of São Paulo, Rua São Nicolau, 210, Diadema 09913-030, SP, BrazilDepartment of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo 05508-900, SP, BrazilDepartment of Biochemistry and Organic Chemistry, Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Avenida João Dagnone, 1100, São Carlos 13563-120, SP, BrazilThe 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<sup>11</sup>, Lys<sup>12</sup>,Lys<sup>13</sup>-(pBthTX-I)<sub>2</sub>K (<b>(pBthTX-I)<sub>2</sub>K)</b>) and derivatives against SARS-CoV-2 are reported. The lead peptide <b>(pBthTX-I)<sub>2</sub>K</b> and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC<sub>50</sub> = 28–65 µM) and mostly low cytotoxic effect (CC<sub>50</sub> > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (M<sup>pro</sup>) and Papain-Like protease (PL<sup>pro</sup>) inhibitory activities of the peptides were assessed. The synthetic peptides showed PL<sup>pro</sup> inhibition potencies (IC<sub>50</sub>s = 1.0–3.5 µM) and binding affinities (<i>K</i><sub>d</sub> = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against M<sup>pro</sup> (IC<sub>50</sub> > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PL<sup>pro</sup> 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.https://www.mdpi.com/1420-3049/26/16/4896COVID-19SARS-CoV-2inhibitorsPapain-like proteasepeptides |
| spellingShingle | Marjorie C. L. C. Freire 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 Glaucius Oliva Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors Molecules COVID-19 SARS-CoV-2 inhibitors Papain-like protease peptides |
| title | Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors |
| title_full | Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors |
| title_fullStr | Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors |
| title_full_unstemmed | Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors |
| title_short | Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors |
| title_sort | non toxic dimeric peptides derived from the bothropstoxin i are potent sars cov 2 and papain like protease inhibitors |
| topic | COVID-19 SARS-CoV-2 inhibitors Papain-like protease peptides |
| url | https://www.mdpi.com/1420-3049/26/16/4896 |
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