PMID- 31812637 OWN - NLM STAT- MEDLINE DCOM- 20201130 LR - 20201130 IS - 1872-9096 (Electronic) IS - 0166-3542 (Linking) VI - 174 DP - 2020 Feb TI - Discovery of dihydroxyindole-2-carboxylic acid derivatives as dual allosteric HIV-1 Integrase and Reverse Transcriptase associated Ribonuclease H inhibitors. PG - 104671 LID - S0166-3542(19)30555-8 [pii] LID - 10.1016/j.antiviral.2019.104671 [doi] AB - The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 muM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Esposito, Francesca AU - Esposito F AD - Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato (CA), Italy. Electronic address: francescaesposito@unica.it. FAU - Sechi, Mario AU - Sechi M AD - Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy. FAU - Pala, Nicolino AU - Pala N AD - Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy. FAU - Sanna, Adele AU - Sanna A AD - Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy. FAU - Koneru, Pratibha Chowdary AU - Koneru PC AD - Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, 80045, USA. FAU - Kvaratskhelia, Mamuka AU - Kvaratskhelia M AD - Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, 80045, USA. FAU - Naesens, Lieve AU - Naesens L AD - Rega Institute for Medical Research, KU Leuven, B-3000, Leuven, Belgium. FAU - Corona, Angela AU - Corona A AD - Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato (CA), Italy. FAU - Grandi, Nicole AU - Grandi N AD - Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato (CA), Italy. FAU - di Santo, Roberto AU - di Santo R AD - Department of Drug Chemistry and Technologies, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Universita di Roma, Roma, Italy. FAU - D'Amore, Vincenzo Maria AU - D'Amore VM AD - Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy. FAU - Di Leva, Francesco Saverio AU - Di Leva FS AD - Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy. FAU - Novellino, Ettore AU - Novellino E AD - Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy. FAU - Cosconati, Sandro AU - Cosconati S AD - DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi, 43, 81100, Caserta, Italy. FAU - Tramontano, Enzo AU - Tramontano E AD - Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato (CA), Italy. LA - eng GR - R01 AI110310/AI/NIAID NIH HHS/United States GR - U54 GM103368/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191205 PL - Netherlands TA - Antiviral Res JT - Antiviral research JID - 8109699 RN - 0 (Carboxylic Acids) RN - 0 (HIV Integrase Inhibitors) RN - EC 2.7.7.- (HIV Integrase) RN - EC 2.7.7.49 (HIV Reverse Transcriptase) RN - EC 3.1.26.4 (Ribonuclease H, Human Immunodeficiency Virus) RN - YY6481J2FF (p31 integrase protein, Human immunodeficiency virus 1) SB - IM MH - Carboxylic Acids/chemistry/*pharmacology MH - Cell Line MH - Drug Discovery MH - HIV Infections/virology MH - HIV Integrase/metabolism MH - HIV Integrase Inhibitors/chemistry/*pharmacology MH - HIV Reverse Transcriptase/*antagonists & inhibitors MH - HIV-1/*drug effects MH - Humans MH - Molecular Docking Simulation MH - Molecular Structure MH - Ribonuclease H, Human Immunodeficiency Virus/*antagonists & inhibitors MH - Structure-Activity Relationship OTO - NOTNLM OT - Dihydroxyindole-2-carboxylic acids OT - HIV dual inhibitors OT - IN OT - IN-LEDGF binding inhibitors OT - RNase H OT - Sucrose binding site EDAT- 2019/12/10 06:00 MHDA- 2020/12/01 06:00 CRDT- 2019/12/09 06:00 PHST- 2019/09/27 00:00 [received] PHST- 2019/11/29 00:00 [revised] PHST- 2019/12/02 00:00 [accepted] PHST- 2019/12/10 06:00 [pubmed] PHST- 2020/12/01 06:00 [medline] PHST- 2019/12/09 06:00 [entrez] AID - S0166-3542(19)30555-8 [pii] AID - 10.1016/j.antiviral.2019.104671 [doi] PST - ppublish SO - Antiviral Res. 2020 Feb;174:104671. doi: 10.1016/j.antiviral.2019.104671. Epub 2019 Dec 5.