Autor(es):
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
Data: 2021
Identificador Persistente: https://hdl.handle.net/10316/107452
Origem: Estudo Geral - Universidade de Coimbra
Projeto/bolsa:
info:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC/PT;
info:eu-repo/grantAgreement/FCT/OE/SFRH/PT;
info:eu-repo/grantAgreement/FCT/POR_CENTRO/PD/PT;
info:eu-repo/grantAgreement/FCT/OE/SFRH/PT;
Assunto(s): AIDS; BSS-730A; anti-HIV activity; antiplasmodial activity; malaria; spiro-β-lactams; Humans; Plasmodium falciparum; beta-Lactams; Antimalarials; HIV Infections; Plasmodium
Descrição
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.
