HIV-1 reverse transcriptase (RT) — which plays an essential role in the virus life cycle — is the target of two classes of approved anti-HIV drugs. Now, La et al. use a combination of saturation-transfer difference (STD) NMR and in vitro activity assays to screen a library of fragment-sized compounds with the aim of identifying new drug scaffolds targeting HIV-1 RT. Three compounds were found to potently inhibit HIV-1 RT in cell culture, including RT variants displaying resistance to existing clinical inhibitors. Importantly, two of the compounds have mechanisms distinct from those of existing agents, competitively inhibiting HIV-1 RT with respect to the dNTP substrate or the DNA template or primer.
References
La, J. et al. Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening. Proc. Natl Acad. Sci. 112, 6979–6984 (2015)
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Crunkhorn, S. Fragment screening identifies novel HIV-1 RT inhibitors. Nat Rev Drug Discov 14, 460 (2015). https://doi.org/10.1038/nrd4678
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DOI: https://doi.org/10.1038/nrd4678
