Development of HIV -1 protease dimerization inhibitors

You Seok Hwang, Purdue University


The role of HIV protease (PR) in viral replication has made it a significant target for inhibition. Drug resistance problems due to rapid viral mutation rates have led to the development of novel inhibitors with new inhibition mechanisms. One strategy would be to target the dimerization interface of HIV-1 PR because this region is highly conserved. Herein, we describe the efforts to identify the minimal structure necessary for the disruption of HIV-1 PR dimerization. A focused library of 50 compounds based on crosslinked and truncated interfacial HIV PR peptides was synthesized and tested for their inhibitory activities against HIV-1 PR. A number of agents demonstrated better inhibitory efficacy than the full length, cross-linked interfacial peptides with about the half of the molecular weight. A novel strategy to identify potent HIV-1 protease dimerization inhibitors was developed using 12-aminododecanoic acid as a tether to crosslink interfacial peptides. This strategy enabled us to investigate various aspects of HIV-1 PR dimerization inhibitors: D-amino acid residues in inhibitors, the synthesis and evaluation of the inhibitors with multiple mutations, and of the truncated inhibitors. A prodrug strategy targeting HIV-1 PR was developed. Incorporation of guanidinium groups into the inhibitors significantly improved water solubility. Inhibitors with a NBD fluorophore were designed for cellular uptake experiment. Inhibitors with various functional groups were evaluated for cellular uptake and the following efficiency trend was found: guanidinium group (cationic) > free acid group (anionic) > vinyl ester group (neutral).




Chmielewski, Purdue University.

Subject Area

Organic chemistry|Biochemistry

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