Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium

• Autor(a) principal: Bártolo, Inês
• Data de Publicação: 2021
• Outros Autores: 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
• 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
• topic: AIDS; malaria; spiro-β-lactams; BSS-730A; anti-HIV activity; antiplasmodial activity

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.