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

Viruses

Eva Riveira-Muñoz¹  Ester Ballana¹  Roger Badia¹  JoséA. Esté¹  Mauro Carcelli²  Dominga Rogolino²  Enzo Tramontano³  Angela Corona³  Nicole Grandi³  Simona Distinto³  Francesca Esposito³  ClaudiaDel Vecchio⁴  Cristina Parolin⁴ 

[1] AIDS Research Institute—IrsiCaixa, 08916 Badalona, Spain;Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy;Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy;Department of Molecular Medicine, University of Padova, 35122 Padova, Italy;

关键词: HIV-1;    antivirals;    ribonuclease H;    RNase H;    N-acylhydrazone;    RT;   

DOI  :  10.3390/v12070729

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown