A specific protein disorder catalyzer of HIV-1 Nef

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy
  • Acquired Immunodeficiency Syndrome / metabolism*
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • HIV Protease / metabolism
  • HIV-1 / chemistry
  • HIV-1 / drug effects
  • HIV-1 / metabolism*
  • Humans
  • Models, Molecular
  • Protein Denaturation / drug effects
  • Protein Structure, Tertiary / drug effects
  • nef Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
  • nef Gene Products, Human Immunodeficiency Virus / chemistry
  • nef Gene Products, Human Immunodeficiency Virus / metabolism*


  • Anti-HIV Agents
  • nef Gene Products, Human Immunodeficiency Virus
  • nef protein, Human immunodeficiency virus 1
  • HIV Protease