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...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Status: | Published version |
| Publication date: | 2021 |
| Country: | Brasil |
| Institution: | UNESP |
| Repository: | Repositório Institucional da UNESP |
| Language: | English |
| OAI Identifier: | oai:repositorio.unesp.br:11449/229351 |
| Online Access: | http://dx.doi.org/10.3390/molecules26164896 http://hdl.handle.net/11449/229351 |
| Access Level: | Open access |
| Keyword: | COVID-19 Inhibitors Papain-like protease Peptides SARS-CoV-2 |
| _version_ | 1878766755947479040 |
|---|---|
| author | Freire, Marjorie C. L. C. |
| author2 | Noske, Gabriela D. Bitencourt, Natália V. [UNESP] Sanches, Paulo R. S. [UNESP] Santos-Filho, Norival A. [UNESP] 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. [UNESP] Guido, Rafael V. C. Oliva, Glaucius |
| author2_role | author author author author author author author author author author author author author author author author author author author |
| author_browse | Barbosa, Cecília G. Bitencourt, Natália V. [UNESP] Cilli, Eduardo M. [UNESP] Fernandes, Rafaela S. Freire, Marjorie C. L. C. Freitas-Junior, Lucio H. G. Gawriljuk, Victor O. Godoy, Andre S. Guido, Rafael V. C. Juliano, Maria A. Moraes, Carolina B. Nakamura, Aline M. Nogueira, Victor H. R. Noske, Gabriela D. Oliva, Glaucius Peres, Bianca M. Sanches, Paulo R. S. [UNESP] Santos-Filho, Norival A. [UNESP] de Godoy, Mariana O. de Souza, Eduardo P. |
| author_facet | Freire, Marjorie C. L. C. Noske, Gabriela D. Bitencourt, Natália V. [UNESP] Sanches, Paulo R. S. [UNESP] Santos-Filho, Norival A. [UNESP] 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. [UNESP] Guido, Rafael V. C. Oliva, Glaucius |
| author_role | author |
| collection | Repositório Institucional da UNESP |
| 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-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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | BR_e9ffbf47a4ed97ced4e1e7b33ffe0e21 |
| institution | UNESP |
| instname_str | Universidade Estadual Paulista (UNESP) |
| language | eng |
| network_acronym_str | BR |
| network_name_str | Brasil |
| oai_identifier_str | oai:repositorio.unesp.br:11449/229351 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| reponame_str | Repositório Institucional da UNESP |
| spelling | 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. [UNESP] Sanches, Paulo R. S. [UNESP] Santos-Filho, Norival A. [UNESP] 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. [UNESP] Guido, Rafael V. C. Oliva, Glaucius COVID-19 Inhibitors Papain-like protease Peptides SARS-CoV-2 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. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) São Carlos Institute of Physics University of Sao Paulo, Avenida João Dagnone, 1100 Department of Biochemistry and Organic Chemistry Institute of Chemistry São Paulo State University (UNESP) Department of Genetics and Evolution Federal University of São Carlos, Rodovia Washington Luís km 235 The Sao Paulo School of Medicine Federal University of São Paulo, Rua Três de Maio, 100 Department of Microbiology Institute of Biomedical Sciences University of Sao Paulo, Av. Prof. Lineu Prestes, 1374 Department of Pharmaceutical Sciences Federal University of São Paulo, Rua São Nicolau, 210 CAPES: 001 FAPESP: 2013/07600-3 FAPESP: 2018/13588-0 FAPESP: 2020/04602-9 FAPESP: 2020/05761-3 FAPESP: 2020/12519-4 CNPq: 301975/2018-3 http://dx.doi.org/10.3390/molecules26164896 Molecules, v. 26, n. 16, 2021. 1420-3049 http://hdl.handle.net/11449/229351 10.3390/molecules26164896 2-s2.0-85112732983 |
| spellingShingle | Non-toxic dimeric peptides derived from the bothropstoxin-I are potent SARS-CoV-2 and papain-like protease inhibitors Freire, Marjorie C. L. C. COVID-19 Inhibitors Papain-like protease Peptides SARS-CoV-2 |
| status_str | publishedVersion |
| 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 Inhibitors Papain-like protease Peptides SARS-CoV-2 |
| topic_facet | COVID-19 Inhibitors Papain-like protease Peptides SARS-CoV-2 |
| url | http://dx.doi.org/10.3390/molecules26164896 http://hdl.handle.net/11449/229351 |