Probing the interactions of HIV -1 protease dimerization inhibitors

Michael J Bowman, 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 has been difficult. A minimal structure (24) has been determined that is capable of disrupting the dimerization of HIV-1 protease, a model for protein-protein interactions. Chmielewski et al has demonstrated the potential for increasing the potency of 24 with modifications to the side chains, however the peptidic nature of these inhibitors limits their potential as therapeutic agents. Therefore, a study on a series of compounds designed to determine the importance of the amide backbone in the peptidic structure was undertaken. N-methylated variants showed 0 to 2-fold reductions in potency as compared to 24. Additionally, a study of a series of compounds lacking a carboxamide led to the discovery of potent inhibitors containing biphenyl ether moieties in the Phe1 position (Ki = 175 nM ( 64), Ki = 96 nM, (65)). A novel class of cysteine side chain crosslinked inhibitors based on the minimal structure required for dimerization inhibition were designed and synthesized. A total of 25 modifications were prepared, of which many were found to inhibit HIV-1 protease dimerization with Ki values as low as 40 nM (94). Additionally, some of these compounds have desirable increases in aqueous solubility (76, 87). Finally, an inhibitor, based on the minimal structure necessary for dimerization inhibition, was prepared that possesses a photoactivatable side chain on one of the amino acids. This inhibitor was successfully crosslinked to HIV-1 protease and preliminary studies were preformed to determine the site of interaction.

Degree

Ph.D.

Advisors

Chmielewski, Purdue University.

Subject Area

Organic chemistry

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