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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

1
Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy
2
AIDS Research Institute—IrsiCaixa, 08916 Badalona, Spain
3
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy
4
Department of Molecular Medicine, University of Padova, 35122 Padova, Italy
5
CienciaTraducida, 08391 Barcelona, Spain
6
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; https://doi.org/10.3390/v12070729
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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