title: Inhibition of HIV-1 Reverse Transcriptase Dimerization by Small Molecules.
abstract: Because HIV-1 reverse transcriptase is an enzyme whose catalytic activity depends on its heterodimeric structure, this system could be a target for inhibitors that perturb the interactions between the protein subunits, p51 and p66. We previously demonstrated that the small molecule MAS0 reduced the association of the two RT subunits and simultaneously inhibited both the polymerase and ribonuclease H activities. In this study, some analogues of MAS0 were rationally selected by docking studies and evaluated in vitro for their ability to disrupt dimeric assembly. Two inhibitors were identified with improved activity compared to MAS0. This study lays the basis for the rational design of more potent inhibitors of RT dimerization.
authors.affiliation: Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, 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, SS 554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy.
authors.forename: Annalaura
authors.initials: A
authors.lastname: Brai
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Grandi
authors.affiliation: Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.|Department of Department of Biotechnology and Life Sciences, University of Insubria, via Ravasi 2, 21100, Varese, Italy.
authors.forename: Elisa Rita
authors.initials: ER
authors.lastname: Ceresola
authors.affiliation: Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Clementi
authors.affiliation: Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.|Department of Department of Biotechnology and Life Sciences, University of Insubria, via Ravasi 2, 21100, Varese, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Canducci
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy. tramon@unica.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
authors.affiliation: Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy. botta.maurizio@gmail.com.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D006678:HIV / Q000187:drug effects* / Q000201:enzymology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D055503:Protein Multimerization / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013696:Temperature; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054852:Small Molecule Libraries; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: HIV-1 reverse transcriptase; dimerization inhibitors; protein-protein interaction; virtual screening; viruses