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Identification of small peptides inhibiting the integrase‐LEDGF/p75 interaction through targeting the cellular co‐factor |
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| Authors: | Claudia Cavalluzzo Frauke Christ Arnout Voet Ajendra Sharma Brajendra Kumar Singh Kam Y.J. Zhang Eveline Lescrinier Marc De Maeyer Zeger Debyser Erik Van der Eycken |
| Affiliation: | 1. Laboratory for Organic & Microwave‐Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven, , B‐3001 Leuven, Belgium;2. DestiNA Genomics Ltd, , Edinburgh, EH9 3JJ UK;3. Molecular Medicine, Katholieke Universiteit Leuven, , B‐3000 Leuven, Belgium;4. Laboratory for Biomolecular modeling, Katholieke Universiteit Leuven, , B‐3001 Leuven, Belgium;5. Zhang Initiative Research Unit, Advanced Science Institute, , Wako, 351‐0198 Japan;6. Bioorganic Laboratory, Department of Chemistry, University of Delhi, , Delhi, 110 007 India;7. Laboratory for Medicinal Chemistry, University of Leuven (KU Leuven), , B‐3000 Leuven, Belgium |
| 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. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. |
| Keywords: | HIV LEDGF/p75 integrase, protein‐protein interaction solid phase peptide synthesis structure‐activity relationship |