Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission

K.K. Ariën, M. Venkatraj, J. Michiels, J. Joossens, Katleen Vereecken, P. Van der Veken, S. Abdellati, V. Cuylaerts, T. Crucitti, L. Heyndrickx, J. Heeres, K. Augustyns, P.J. Lewi, G. Vanham

Research output: Contribution to journalA1: Web of Science-article

Abstract

OBJECTIVES: Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues. METHODS: From this library, 15 compounds were evaluated in depth using a broad armamentarium of in vitro assays that are part of a preclinical testing algorithm for microbicide development. Antiviral activity was assessed in a cell line, and in primary human cells, against both subtype B and subtype C HIV-1 and against viruses resistant to therapeutic NNRTIs and the candidate NNRTI microbicide dapivirine. Toxicity towards primary blood-derived cells, cell lines originating from the female reproductive tract and female genital microflora was also studied. RESULTS AND CONCLUSIONS: We identified several compounds with highly potent antiviral activity and toxicity profiles that are superior to that of dapivirine. In particular, compound UAMC01398 is an interesting new candidate that warrants further investigation because of its superior toxicity profile and potent activity against dapivirine-resistant viruses.
Original languageEnglish
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number9
Pages (from-to)2038-2047
Number of pages10
ISSN0305-7453
DOIs
Publication statusPublished - 2013

Keywords

  • Viral diseases
  • HIV
  • AIDS
  • Disease transmission-sexual
  • Prevention
  • Drug development
  • Pre-exposure
  • Prophylaxis
  • Microbicides
  • Non-nucleoside
  • Reverse transcriptase inhibitors
  • Diaryltriazine
  • Evaluation
  • In vitro
  • Assays
  • Subtype B
  • Subtype C
  • Dapivirine
  • Toxicity

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