title: New insights into the interaction between pyrrolyl diketoacids and HIV-1 integrase active site and comparison with RNase H.
abstract: HIV-1 integrase (IN) inhibitors are one of the most recent innovations in the treatment of HIV infection. The selection of drug resistance viral strains is however a still open issue requiring constant efforts to identify new anti-HIV-1 drugs. Pyrrolyl diketo acid (DKA) derivatives inhibit HIV-1 replication by interacting with the Mg2+cofactors within the HIV-1 IN active site or within the HIV-1 reverse-transcriptase associated ribonuclease H (RNase H) active site. While the interaction mode of pyrrolyl DKAs with the RNase H active site has been recently reported and substantiated by mutagenesis experiments, their interaction within the IN active site still lacks a detailed understanding. In this study, we investigated the binding mode of four pyrrolyl DKAs to the HIV-1 IN active site by molecular modeling coupled with site-directed mutagenesis studies showing that the DKA pyrrolyl scaffold primarily interacts with the IN amino residues P145, Q146 and Q148. Importantly, the tested DKAs demonstrated good effectiveness against HIV-1 Raltegravir resistant Y143A and N155H INs, thus showing an interaction pattern with relevant differences if compared with the first generation IN inhibitors. These data provide precious insights for the design of new HIV inhibitors active on clinically selected Raltegravir resistant variants. Furthermore, this study provides new structural information to modulate IN and RNase H inhibitory activities for development of dual-acting anti-HIV agents.
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano, 49 80131, Naples, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: di Leva
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato, Italy; LBPA, ENS Cachan, CNRS, 61 Avenue du président Wilson, 94235, Cachan Cedex, France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rigogliuso
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pescatori
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Valentina Noemi
authors.initials: VN
authors.lastname: Madia
authors.affiliation: LBPA, ENS Cachan, CNRS, 61 Avenue du président Wilson, 94235, Cachan Cedex, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Subra
authors.affiliation: LBPA, ENS Cachan, CNRS, 61 Avenue du président Wilson, 94235, Cachan Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delelis
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Cadeddu
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.affiliation: DiSTABiF, Seconda Università di Napoli, Via Vivaldi, 43, 81100, Caserta, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano, 49 80131, Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: di Santo
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato, Italy. Electronic address: tramon@unica.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology; D019427:HIV Integrase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016914:Ribonuclease H / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011758:Pyrroles; D019427:HIV Integrase; D016914:Ribonuclease H; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: Diketoacid; HIV; Inhibition; Integrase; RNase H; Ribonuclease H