Peptide inhibitors of HIV -1 integrase activity and dimerization

Lei Zhao, Purdue University

Abstract

Protein-protein interactions are increasingly being studied as targets for therapeutic intervention of many biological processes. However, the design of agents to disrupt these biologically important interactions is still in its infancy. Herein we described efforts to disrupt the dimer of HIV-1 integrase. Five interfacial peptides have been synthesized and tested for their inhibition against HIV-1 integrase. Three of these were found to be potent inhibitors. Their mode of inhibition was studied using two novel methods, and it was proven that the compounds are able to disrupt the dimerization of HIV-1 integrase. Two of the peptide dimerization inhibitors of HIV-1 integrase are spatially close to one another. In an effort to increase potency, these peptides were crosslinked to mimic a larger region of the dimerization interface. A series of compounds was synthesized utilizing various flexible and rigid tethers. A subset of the crosslinked peptides with rigid tethers were found to have increased potency as compared to the starting uncrosslinked peptides with a dimerization inhibition mechanism. Aib mutations were made to one of the peptide inhibitors. The mutation resulted in the formation of a 310-helix instead of the desired α-helix, and led to a drop in potency. Finally, changes were made within a peptide dimerization inhibitor of HIV-1 integrase to include a cell penetrating sequence, in an effort to improve its cellular uptake. Flow cytometry data demonstrated its enhanced uptake within a T-lymphocyte cell line.

Degree

Ph.D.

Advisors

Chmielewski, Purdue University.

Subject Area

Organic chemistry

COinS