A specific protein disorder catalyzer of HIV-1 Nef

Adrien Lugari, Sebastian Breuer, Thibault Coursindel, Sandrine Opi, Audrey Restouin, Xiaoli Shi, Alexis Nazabal, Bruce E. Torbett, Jean Martinez, Yves Collette, Isabelle Parrot, Stefan T. Arold*, Xavier Morelli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The HIV-1 auxiliary protein Nef is required for the onset and progression of AIDS in HIV-1-infected persons. Here, we have deciphered the mode of action of a second-generation inhibitor of Nef, DLC27-14, presenting a competitive IC 50 of ∼16 μM measured by MALDI-TOF experiments. Thermal protein denaturation experiments revealed a negative effect on stability of Nef in the presence of a saturating concentration of the inhibitor. The destabilizing action of DLC27-14 was confirmed by a HIV protease-based experiment, in which the protease sensitivity of DLC27-14-bound Nef was three times as high as that of apo Nef. The only compatible docking modes of action for DLC27-14 suggest that DLC27-14 promotes an opening of two α-helices that would destabilize the Nef core domain. DLC27-14 thus acts as a specific protein disorder catalyzer that destabilizes the folded conformation of the protein. Our results open novel avenues toward the development of next-generation Nef inhibitors.

Original languageEnglish (US)
Pages (from-to)7401-7406
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number24
DOIs
StatePublished - Dec 15 2011

Keywords

  • HIV-1 Nef inhibitor
  • Mass spectrometry
  • Molecular modeling
  • Protein-protein interaction inhibitor
  • Thermostability

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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