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Bioorg Med Chem. 2011 Dec 15;19(24):7401-6. doi: 10.1016/j.bmc.2011.10.051. Epub 2011 Oct 20.

A specific protein disorder catalyzer of HIV-1 Nef.

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IMR Laboratory, CNRS-UPR 3243, Centre National de Recherche Scientifique, Institut de Microbiologie de Méditerranée and Aix-Marseille Universités, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.


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.

[Indexed for MEDLINE]

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