title: Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication.
abstract: The interaction between the human immunodeficiency virus (HIV) integrase (IN) and its cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is crucial for HIV replication. While recently discovered LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in IN, it remained to be demonstrated whether LEDGF/p75 by itself can be targeted. By phage display we identified cyclic peptides (CPs) as the first LEDGF/p75 ligands that inhibit the LEDGF/p75-IN interaction. The CPs inhibit HIV replication in different cell lines without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration and its inhibition by LEDGINs, CP64, and CP65 block HIV replication primarily by inhibiting the integration step. The CPs retained activity against HIV strains resistant to raltegravir or LEDGINs. Saturation transfer difference (STD) NMR showed residues in CP64 that strongly interact with LEDGF/p75 but not with HIV IN. Mutational analysis identified tryptophan as an important residue responsible for the activity of the peptides. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as novel therapeutic strategy and the CPs thereby serve as scaffold for future development of new HIV therapeutics.
authors: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, K.U.Leuven and IRC Kulak, Flanders, Belgium.
authors: Belete A
authors: BA
authors: Desimmie
authors: Michael
authors: M
authors: Humbert
authors: Eveline
authors: E
authors: Lescrinier
authors: Jelle
authors: J
authors: Hendrix
authors: Sofie
authors: S
authors: Vets
authors: Rik
authors: R
authors: Gijsbers
authors: Ruth M
authors: RM
authors: Ruprecht
authors: Ursula
authors: U
authors: Dietrich
authors: Zeger
authors: Z
authors: Debyser
authors: Frauke
authors: F
authors: Christ
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D061505:Cell Surface Display Techniques; D017124:Conserved Sequence; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011485:Protein Binding; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019380:Anti-HIV Agents; C504649:PSIP1 protein, human; D019151:Peptide Library; D010456:Peptides, Cyclic; D014157:Transcription Factors; D019427:HIV Integrase