title: Identification of small peptides inhibiting the integrase-LEDGF/p75 interaction through targeting the cellular co-factor.
abstract: The integration of the viral DNA into the host genome is one of the essential steps in the HIV replication cycle. This process is mediated by the viral enzyme integrase (IN) and lens epithelium-derived growth factor (LEDGF/p75). LEDGF/p75 has been identified as a crucial cellular co-factor of integration that acts by tethering IN to the cellular chromatin. Recently, circular peptides were identified that bind to the C-terminal domain of IN and disrupt the interaction with LEDGF/p75. Starting from the circular peptides, we identified a short peptidic sequence able to inhibit the LEDGF/p75-IN interaction at low μM concentration through its binding to the IN binding site of LEDGF/p75. This discovery can lead to the synthesis of peptidomimetics with high anti-HIV activity targeting the cellular co-factor LEDGF/p75 and not the viral protein IN.
authors.affiliation: Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium; DestiNA Genomics Ltd, West Mains Road, Edinburgh, EH9 3JJ, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cavalluzzo
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Arnout
authors.initials: A
authors.lastname: Voet
authors.forename: Ajendra
authors.initials: A
authors.lastname: Sharma
authors.forename: Brajendra Kumar
authors.initials: BK
authors.lastname: Singh
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.forename: Marc
authors.initials: M
authors.lastname: De Maeyer
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Erik
authors.initials: E
authors.lastname: Van der Eycken
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002843:Chromatin / Q000235:genetics; D004279:DNA, Viral / Q000187:drug effects; D006678:HIV / Q000378:metabolism* / Q000472:pathogenicity; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D016662:Virus Integration / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D002843:Chromatin; D004279:DNA, Viral; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C119380:lens epithelium-derived growth factor; D019426:Integrases
keywords: HIV; LEDGF/p75; integrase, protein-protein interaction; solid phase peptide synthesis; structure-activity relationship