Depollier J, Hourdou ML, Herrada-Aldrian G, Restle T, Divita G; HIV DRP Symposium Antiviral Drug Resistance (4th: 2003: Chantilly, Va.).

Program Abstr HIV DRP Symp Antivir Drug Resist. 2003 Dec 7-10; 4: Abstract no. 48.

CRBM CNRS FRE2593 1919, route de Mende 34293 Montpellier cedex 5, France

HIV reverse transcriptase (RT) dimerization constitutes an attractive target for chemotherapeutic intervention in HIV infection. Based on the knowledge of both the structure and dimerization mechanism of RT, we have proposed a new class of inhibitors based on short peptide motifs derived from the dimer interface between the two "connection" sub-domains of RT. We have demonstrated that a short 10-residue peptide (pep-7) complexed to a carrier peptide (MPG) is able to inhibit replication of HIV-1 and HIV-2 isolates at very low concentrations (nanomolar range). To improve pep-7 efficiency, we have investigated the mechanism through which it prevents RT dimerization, by combining fluorescence spectroscopy and chromatography. We show that pep-7 interacts preferentially with a Trp-cluster located in p51 "connection" sub-domain and demonstrate that residues W24 and F61 in p51 are required for this interaction. Mutations W24G, F61G and W24G/F61G dramatically affect RT stability and limit pep-7 binding. A pep-7-derived peptides screening with different mutations at hydrophobic positions has revealed critical residues in pep-7 sequence for its inhibition of RT. Based on both our biochemical results and our 3D structural model of the RT/pep-7 complex, we suggest that inhibition is associated with a conformational change affecting p51 connection and fingers sub-domains. Taken together, our results indicate that pep-7/MPG complex meets the criteria of a promising new antiviral agent to prevent HIV propagation as well as multidrug-resistant HIVs. In order to improve the therapeutic potency of this drug, we have designed a chimeric peptide which mimics pep-7 structure and exhibits MPG properties for cell internalization. Several peptide sequences have been tested and the most promising chimer obtained so far exhibits a similar pep-7/MPG efficiency. We believe that this new peptide will enable the development of an efficient therapeutic compound designed to target HIV-RT, while avoiding the emergence of resistant strains. Acknowledgements: This work has been supported by grant from the Agence Nationale de Recherches sur le Sida (ANRS).

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Amino Acid Sequence
• Antiviral Agents
• Dimerization
• HIV-1
• HIV-2
• Peptides
• RNA-Directed DNA Polymerase

Other ID:

• GWAIDS0028841

UI: 102268473

From Meeting Abstracts