title: A specific protein disorder catalyzer of HIV-1 Nef.
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.
authors: 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.
authors: Adrien
authors: A
authors: Lugari
authors: Sebastian
authors: S
authors: Breuer
authors: Thibault
authors: T
authors: Coursindel
authors: Sandrine
authors: S
authors: Opi
authors: Audrey
authors: A
authors: Restouin
authors: Xiaoli
authors: X
authors: Shi
authors: Alexis
authors: A
authors: Nazabal
authors: Bruce E
authors: BE
authors: Torbett
authors: Jean
authors: J
authors: Martinez
authors: Yves
authors: Y
authors: Collette
authors: Isabelle
authors: I
authors: Parrot
authors: Stefan T
authors: ST
authors: Arold
authors: Xavier
authors: X
authors: Morelli
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000378:metabolism*; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D016333:HIV Protease / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011489:Protein Denaturation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D016333:HIV Protease