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Open AccessArticle

Targeting HIV-1 RNase H: N’-(2-Hydroxy-benzylidene)-3,4,5-Trihydroxybenzoylhydrazone as Selective Inhibitor Active against NNRTIs-Resistant Variants

Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy
AIDS Research Institute—IrsiCaixa, 08916 Badalona, Spain
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy
Department of Molecular Medicine, University of Padova, 35122 Padova, Italy
CienciaTraducida, 08391 Barcelona, Spain
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), 09042 Monserrato, Cagliari, Italy
Author to whom correspondence should be addressed.
Viruses 2020, 12(7), 729;
Received: 30 April 2020 / Revised: 28 June 2020 / Accepted: 1 July 2020 / Published: 6 July 2020
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
HIV-1 infection requires life-long treatment and with 2.1 million new infections/year, faces the challenge of an increased rate of transmitted drug-resistant mutations. Therefore, a constant and timely effort is needed to identify new HIV-1 inhibitors active against drug-resistant variants. The ribonuclease H (RNase H) activity of HIV-1 reverse transcriptase (RT) is a very promising target, but to date, still lacks an efficient inhibitor. Here, we characterize the mode of action of N’-(2-hydroxy-benzylidene)-3,4,5-trihydroxybenzoylhydrazone (compound 13), an N-acylhydrazone derivative that inhibited viral replication (EC50 = 10 µM), while retaining full potency against the NNRTI-resistant double mutant K103N-Y181C virus. Time-of-addition and biochemical assays showed that compound 13 targeted the reverse-transcription step in cell-based assays and inhibited the RT-associated RNase H function, being >20-fold less potent against the RT polymerase activity. Docking calculations revealed that compound 13 binds within the RNase H domain in a position different from other selective RNase H inhibitors; site-directed mutagenesis studies revealed interactions with conserved amino acid within the RNase H domain, suggesting that compound 13 can be taken as starting point to generate a new series of more potent RNase H selective inhibitors active against circulating drug-resistant variants. View Full-Text
Keywords: HIV-1; antivirals; ribonuclease H; RNase H; N-acylhydrazone; RT HIV-1; antivirals; ribonuclease H; RNase H; N-acylhydrazone; RT
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Corona, A.; Ballana, E.; Distinto, S.; Rogolino, D.; Del Vecchio, C.; Carcelli, M.; Badia, R.; Riveira-Muñoz, E.; Esposito, F.; Parolin, C.; Esté, J.A.; Grandi, N.; Tramontano, E. Targeting HIV-1 RNase H: N’-(2-Hydroxy-benzylidene)-3,4,5-Trihydroxybenzoylhydrazone as Selective Inhibitor Active against NNRTIs-Resistant Variants. Viruses 2020, 12, 729.

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