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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
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.
Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy..
Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.;Aalborg Univ, Dept Chem & Biosci, Aalborg, Denmark..
Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
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2018 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 9, no 3, p. 562-575Article in journal (Refereed) Published
Abstract [en]

Persistent HIV infection requires lifelong 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 with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme 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 the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 mu M with three hits exhibiting IC50 values < 10 mu M. The most active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 mu M and exhibits a 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, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY , 2018. Vol. 9, no 3, p. 562-575
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Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-351761DOI: 10.1039/c7md00600dISI: 000428670100016OAI: oai:DiVA.org:uu-351761DiVA, id: diva2:1212148
Available from: 2018-06-01 Created: 2018-06-01 Last updated: 2018-06-01Bibliographically approved

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Poongavanam, Vasanthanathan

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