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Title: Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication
Authors: Desimmie, Belete Ayele
Humbert, Michael
Lescrinier, Eveline
Hendrix, Jelle
Vets, Sofie
Gijsbers, Rik
Ruprecht, Ruth M
Dietrich, Ursula
Debyser, Zeger
Christ, Frauke # ×
Issue Date: Nov-2012
Publisher: Academic Press
Series Title: Molecular Therapy vol:20 issue:11 pages:2064-2075
Article number: 10.1038/mt.2012.132
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.
URI: 
ISSN: 1525-0016
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
Medicinal Chemistry (Rega Institute)
× corresponding author
# (joint) last author

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