title: 4-[1-(4-Fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid as a prototype to develop dual inhibitors of HIV-1 integration process.
abstract: In recent years several potent HIV-1 integrase (IN) inhibitors have been identified and after the successful clinical use of raltegravir, they have gained a definitive place in the treatment of HIV-1 infection. Yet, there is a continuous effort to design newer inhibitors that target different steps in the integration process. Furthermore, the increased understanding of IN structural biology has opened novel approaches to inhibit IN, such as targeting its multimerization or interaction with cellular cofactors. On these bases, we have concentrated our research on the identification of small molecules able to inhibit two different stages of the integration process: the IN strand-transfer phase and the IN-LEDGF/p75 interaction. We found that the 4-[1-(4-fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (CHI-1043) is an interesting anti-HIV agent exhibiting dual inhibitory effects. This work has suggested the possibility of also constructing an integration dual inhibitor using a design-in strategy.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.forename: Sara
authors.initials: S
authors.lastname: De Grazia
authors.forename: Francesca
authors.initials: F
authors.lastname: Morreale
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D002460:Cell Line; D015658:HIV Infections / Q000378:metabolism / Q000821:virology*; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D006885:Hydroxybutyrates / Q000138:chemical synthesis*; D007211:Indoles / Q000138:chemical synthesis*; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D016662:Virus Integration / Q000187:drug effects*
chemical_list: C569032:4-(1-(4-fluorobenzyl)-4-hydroxy-1H-indol-3-yl)-2-hydroxy-4-oxobut-2-enoic acid; D019428:HIV Integrase Inhibitors; D006885:Hydroxybutyrates; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase