Spiro-ß-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/10451/58948 |
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-ß-lactam BSS-730A Displays Potent Activity against HIV and PlasmodiumAIDSmalariaspiro-β-lactamsBSS-730Aanti-HIV activityantiplasmodial activityThe 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.Coimbra Chemistry Centre (CQC), University of Coimbra, Portugal, is supported by the Portuguese Agency for Scientific Research, “Fundação para a Ciência e a Tecnologia” (FCT) through Projects UIDB/00313/2020 and UIDP/00313/2020, cofunded by COMPETE2020-UE. iMed. ULisboa, Faculdade de Farmacia de Lisboa, Portugal, is supported by the Portuguese Agency for Scientific Research, “Fundação para a Ciência e a Tecnologia” (FCT) through Projects UIDB/04138/2020 and UIDP/04138/2020. FCT is also acknowledged for Project PTDC-SAU-INF-29550-2017 to M.P., for a postdoc fellowship to I.B. (SFRH/BPD/76225/2011) and for Ph.D. fellowships to N.A. (PD/BD/135287/2017) and A.A. (SFRH/BD/128910/2017). The funders had no role in study design, data collection, and interpretation, nor the decision to submit the work for publication. We acknowledge the UC1010 NMR facility for producing the NMR data (www.nmrccc.uc.pt) and Filipa Teixeira for producing Plasmodium-infected Anopheles mosquitoes for sporozoite isolation.ACS PublishingRepositório da Universidade de LisboaBártolo, InêsSantos, Bruna S.Fontinha, DianaMachado, MartaFrancisco, DeniseSepodes, BrunoRocha, JoaoMota-Filipe, HélderPinto, RuiFigueira, Maria-EduardoBarroso, HelenaNascimento, TeresaMatos, António P. Alves deAlves, AméricoAlves, Nuno G.Simões, Carlos J. V.Prudêncio, MiguelMelo, Teresa M. V. D. Pinho ETaveira, Nuno2023-08-21T18:59:07Z2021-01-042023-02-03T12:14:40Z2021-01-04T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/58948engBártolo I, Santos BS, Fontinha D, Machado M, Francisco D, Sepodes B, et al. Spiro-β-lactam bss-730a displays potent activity against hiv and plasmodium. ACS Infect Dis [Internet]. 12 de fevereiro de 2021;7(2):421–34. Disponível em: https://pubs.acs.org/doi/10.1021/acsinfecdis.0c007682373-8227cv-prod-309187610.1021/acsinfecdis.0c007682-s2.0-85099655355metadata only accessinfo: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:RCAAP2023-11-08T17:03:32Zoai:repositorio.ul.pt:10451/58948Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:06:41.229448Repositório 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-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title |
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
spellingShingle |
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium Bártolo, Inês AIDS malaria spiro-β-lactams BSS-730A anti-HIV activity antiplasmodial activity |
title_short |
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_full |
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_fullStr |
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_full_unstemmed |
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium |
title_sort |
Spiro-ß-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, Joao Mota-Filipe, Hélder Pinto, Rui Figueira, Maria-Eduardo Barroso, Helena Nascimento, Teresa Matos, António P. Alves de Alves, Américo Alves, Nuno G. Simões, Carlos J. V. Prudêncio, Miguel Melo, Teresa M. V. D. Pinho E Taveira, Nuno |
author_role |
author |
author2 |
Santos, Bruna S. Fontinha, Diana Machado, Marta Francisco, Denise Sepodes, Bruno Rocha, Joao Mota-Filipe, Hélder Pinto, Rui Figueira, Maria-Eduardo Barroso, Helena Nascimento, Teresa Matos, António P. Alves de Alves, Américo Alves, Nuno G. Simões, Carlos J. V. Prudêncio, Miguel Melo, Teresa M. V. D. Pinho E Taveira, Nuno |
author2_role |
author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Bártolo, Inês Santos, Bruna S. Fontinha, Diana Machado, Marta Francisco, Denise Sepodes, Bruno Rocha, Joao Mota-Filipe, Hélder Pinto, Rui Figueira, Maria-Eduardo Barroso, Helena Nascimento, Teresa Matos, António P. Alves de Alves, Américo Alves, Nuno G. Simões, Carlos J. V. Prudêncio, Miguel Melo, Teresa M. V. D. Pinho E Taveira, Nuno |
dc.subject.por.fl_str_mv |
AIDS malaria spiro-β-lactams BSS-730A anti-HIV activity antiplasmodial activity |
topic |
AIDS malaria spiro-β-lactams BSS-730A anti-HIV activity antiplasmodial activity |
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 |
2021-01-04 2021-01-04T00:00:00Z 2023-08-21T18:59:07Z 2023-02-03T12:14:40Z |
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/10451/58948 |
url |
http://hdl.handle.net/10451/58948 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Bártolo I, Santos BS, Fontinha D, Machado M, Francisco D, Sepodes B, et al. Spiro-β-lactam bss-730a displays potent activity against hiv and plasmodium. ACS Infect Dis [Internet]. 12 de fevereiro de 2021;7(2):421–34. Disponível em: https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00768 2373-8227 cv-prod-3091876 10.1021/acsinfecdis.0c00768 2-s2.0-85099655355 |
dc.rights.driver.fl_str_mv |
metadata only access info:eu-repo/semantics/openAccess |
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metadata only access |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
ACS Publishing |
publisher.none.fl_str_mv |
ACS Publishing |
dc.source.none.fl_str_mv |
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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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