Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/107452 https://doi.org/10.1021/acsinfecdis.0c00768 |
Resumo: | The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 μM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 μM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium. |
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Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and PlasmodiumAIDSBSS-730Aanti-HIV activityantiplasmodial activitymalariaspiro-β-lactamsHumansPlasmodium falciparumbeta-LactamsAntimalarialsHIV InfectionsPlasmodiumThe high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 μM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 μM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium.ACS American Chemical Society2021-02-12info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/107452http://hdl.handle.net/10316/107452https://doi.org/10.1021/acsinfecdis.0c00768eng2373-82272373-8227https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00768Bártolo, InêsSantos, Bruna SFontinha, DianaMachado, MartaFrancisco, DeniseSepodes, BrunoRocha, JoãoMota-Filipe, HélderPinto, RuiFigueira, Maria E.Barroso, HelenaNascimento, TeresaAlves de Matos, António P.Alves, Américo J. S.Alves, Nuno G.Simões, Carlos J. V.Prudêncio, MiguelPinho e Melo, Teresa M. V. D.Taveira, Nunoinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-17T08:53:01Zoai:estudogeral.uc.pt:10316/107452Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:23:48.420975Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
spellingShingle |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium Bártolo, Inês AIDS BSS-730A anti-HIV activity antiplasmodial activity malaria spiro-β-lactams Humans Plasmodium falciparum beta-Lactams Antimalarials HIV Infections Plasmodium |
title_short |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_full |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_fullStr |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_full_unstemmed |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_sort |
Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
author |
Bártolo, Inês |
author_facet |
Bártolo, Inês Santos, Bruna S Fontinha, Diana Machado, Marta Francisco, Denise Sepodes, Bruno Rocha, João Mota-Filipe, Hélder Pinto, Rui Figueira, Maria E. Barroso, Helena Nascimento, Teresa Alves de Matos, António P. Alves, Américo J. S. Alves, Nuno G. Simões, Carlos J. V. Prudêncio, Miguel Pinho e Melo, Teresa M. V. D. Taveira, Nuno |
author_role |
author |
author2 |
Santos, Bruna S Fontinha, Diana Machado, Marta Francisco, Denise Sepodes, Bruno Rocha, João Mota-Filipe, Hélder Pinto, Rui Figueira, Maria E. Barroso, Helena Nascimento, Teresa Alves de Matos, António P. Alves, Américo J. S. Alves, Nuno G. Simões, Carlos J. V. Prudêncio, Miguel Pinho e Melo, Teresa M. V. D. Taveira, Nuno |
author2_role |
author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Bártolo, Inês Santos, Bruna S Fontinha, Diana Machado, Marta Francisco, Denise Sepodes, Bruno Rocha, João Mota-Filipe, Hélder Pinto, Rui Figueira, Maria E. Barroso, Helena Nascimento, Teresa Alves de Matos, António P. Alves, Américo J. S. Alves, Nuno G. Simões, Carlos J. V. Prudêncio, Miguel Pinho e Melo, Teresa M. V. D. Taveira, Nuno |
dc.subject.por.fl_str_mv |
AIDS BSS-730A anti-HIV activity antiplasmodial activity malaria spiro-β-lactams Humans Plasmodium falciparum beta-Lactams Antimalarials HIV Infections Plasmodium |
topic |
AIDS BSS-730A anti-HIV activity antiplasmodial activity malaria spiro-β-lactams Humans Plasmodium falciparum beta-Lactams Antimalarials HIV Infections Plasmodium |
description |
The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 μM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 μM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-02-12 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/107452 http://hdl.handle.net/10316/107452 https://doi.org/10.1021/acsinfecdis.0c00768 |
url |
http://hdl.handle.net/10316/107452 https://doi.org/10.1021/acsinfecdis.0c00768 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2373-8227 2373-8227 https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00768 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
ACS American Chemical Society |
publisher.none.fl_str_mv |
ACS American Chemical Society |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799134124435308544 |