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Structure-guided approach identifies a novel class of HIV-1 Ribonuclease H inhibitors: Binding mode insights through magnesium complexation and site-directed mutagenesis studies

Abstract

HIV persistent infection requires a life-long treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors endowed with innovative mechanisms. The HIV-1 Reverse Transcriptase (RT) associated Ribonuclease H (RNase H) is the only viral encoded enzymatic activity that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of 45 compounds selected for experimental testing, 15 of these inhibited the RNase H function below 100 µM with three hits possessing IC50 values < 10 µM. The most active compound AA inhibits HIV-1 RNase H with an IC50 of 5.1 µM, and possesses Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds, for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, Trp (406, 426 and 535) and polar interactions with Arg557 and with the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.

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Publication details

The article was received on 25 Nov 2017, accepted on 29 Jan 2018 and first published on 01 Feb 2018


Article type: Research Article
DOI: 10.1039/C7MD00600D
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Structure-guided approach identifies a novel class of HIV-1 Ribonuclease H inhibitors: Binding mode insights through magnesium complexation and site-directed mutagenesis studies

    V. Poongavanam, A. Corona, C. Svendsen, L. Scipione, N. Grandi, F. Pandolfi, R. Di Santo, R. Costi, F. Esposito, E. Tramontano and J. Kongsted, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C7MD00600D

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