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

Inês Bártolo, Bruna S. Santos, Diana Fontinha, Marta MacHado, Denise Francisco, Bruno Sepodes, João Rocha, Hélder Mota-Filipe, Rui Pinto, Maria E. Figueira, Helena Barroso, Teresa Nascimento, António P. Alves De Matos, Américo J.S. Alves, Nuno G. Alves, Carlos J.V. Simões, Miguel Prudêncio, Teresa M.V.D. Pinho E Melo, Nuno Taveira

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)421-434
Number of pages14
JournalACS Infectious Diseases
Volume7
Issue number2
DOIs
Publication statusPublished - 12 Feb 2021

Keywords

  • AIDS
  • BSS-730A
  • anti-HIV activity
  • antiplasmodial activity
  • malaria
  • spiro-β-lactams

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