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Title: | Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium | Authors: | 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 |
Keywords: | AIDS; BSS-730A; anti-HIV activity; antiplasmodial activity; malaria; spiro-β-lactams | Issue Date: | 12-Feb-2021 | Publisher: | ACS American Chemical Society | Project: | info:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC/SAU-INF/29550/2017/PT/Enabling strategies for enhanced whole-sporozoite malaria vaccines info:eu-repo/grantAgreement/FCT/OE/SFRH/BPD/76225/2011/PT/DESENVOLVIMENTO DE NOVOS MICROBICIDAS PARA PREVENIR A INFECÇÃO POR VIH info:eu-repo/grantAgreement/FCT/POR_CENTRO/PD/BD/135287/2017/PT/Broadening the spectrum of spito-B-lactams antiviral activity: from new targets identification to the discovery of new compounds with anti-influenza activity. info:eu-repo/grantAgreement/FCT/OE/SFRH/BD/128910/2017/PT/Novel spiro-lactams as new antimicrobial agents UIDB/04138/2020 UIDB/00313/2020 UIDP/00313/2020 |
Serial title, monograph or event: | Infectious Diseases | Volume: | 7 | Issue: | 2 | Abstract: | 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. | URI: | https://hdl.handle.net/10316/107452 | ISSN: | 2373-8227 2373-8227 |
DOI: | 10.1021/acsinfecdis.0c00768 | Rights: | embargoedAccess |
Appears in Collections: | I&D CQC - Artigos em Revistas Internacionais |
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Bartolo2021ACSInfectDis.pdf | 1.86 MB | Adobe PDF | View/Open |
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