title: Chelation Motifs Affecting Metal-dependent Viral Enzymes:N'-acylhydrazone Ligands as Dual Target Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection, still represent a serious global health emergency. The chronic toxicity derived from the current anti-retroviral therapy limits the prolonged use of several antiretroviral agents, continuously requiring the discovery of new antiviral agents with innovative strategies of action. In particular, the development of single molecules targeting two proteins (dual inhibitors) is one of the current main goals in drug discovery. In this contest, metal-chelating molecules have been extensively explored as potential inhibitors of viral metal-dependent enzymes, resulting in some important classes of antiviral agents. Inhibition of HIV Integrase (IN) is, in this sense, paradigmatic. HIV-1 IN and Reverse Transcriptase-associated Ribonuclease H (RNase H) active sites show structural homologies, with the presence of two Mg(II) cofactors, hence it seems possible to inhibit both enzymes by means of chelating ligands with analogous structural features. Here we present a series ofN'-acylhydrazone ligands with groups able to chelate the Mg(II) hard Lewis acid ions in the active sites of both the enzymes, resulting in dual inhibitors with micromolar and even nanomolar activities. The most interesting identifiedN'-acylhydrazone analog, compound18, shows dual RNase H-IN inhibition and it is also able to inhibit viral replication in cell-based antiviral assays in the low micromolar range. Computational modeling studies were also conducted to explore the binding attitudes of some model ligands within the active site of both the enzymes.
authors.affiliation: Department of Chemistry, University of Parma Parma, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Carcelli
authors.affiliation: Department of Chemistry, University of ParmaParma, Italy; Research Interuniversity Consortium Chemistry of Metals in Biological Systems Parma Unit, University of ParmaParma, Italy.
authors.forename: Dominga
authors.initials: D
authors.lastname: Rogolino
authors.affiliation: Department of Chemistry, University of ParmaParma, Italy; Research Interuniversity Consortium Chemistry of Metals in Biological Systems Parma Unit, University of ParmaParma, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Gatti
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari Sassari, Italy.
authors.forename: Nicolino
authors.initials: N
authors.lastname: Pala
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato Cagliari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato Cagliari, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Caredda
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di MonserratoCagliari, Italy; Genetics and Biomedical Research institute, National Research CouncilMonserrato, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
authors.affiliation: Rega Institute for Medical Research, KU Leuven Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Rega Institute for Medical Research, KU Leuven Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
keywords: HIV-1 integrase; RNase H; acylhydrazone; antiviral agents; chelating pharmacophore; dual inhibitors