1. Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium
- Author
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Teresa Nascimento, Denise Francisco, Helena Barroso, Américo J. S. Alves, Carlos J. V. Simões, João Rocha, Diana Fontinha, Miguel Prudêncio, Nuno G. Alves, Marta Machado, Bruno Sepodes, Helder Mota-Filipe, Bruna S. Santos, António P Alves de Matos, Rui Pinto, Nuno Taveira, Teresa M. V. D. Pinho e Melo, Maria Eduardo Figueira, and Inês Bártolo
- Subjects
0301 basic medicine ,Plasmodium ,030106 microbiology ,Plasmodium falciparum ,HIV Infections ,Drug resistance ,beta-Lactams ,03 medical and health sciences ,Antimalarials ,Acquired immunodeficiency syndrome (AIDS) ,Medicine ,Humans ,IC50 ,biology ,business.industry ,biology.organism_classification ,medicine.disease ,Virology ,Entry inhibitor ,030104 developmental biology ,Infectious Diseases ,Mechanism of action ,Tolerability ,sense organs ,medicine.symptom ,business ,Malaria ,medicine.drug - 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.
- Published
- 2021