Development of the HIV -1 protease dimerization inhibitors using focused library approaches

Young-Wan Ham, Purdue University

Abstract

Although there is growing literature on the structural nature of protein-protein interactions, the design of agents to disrupt these interactions is in its infancy. Using HIV-1 protease as a model we have developed a minimal structure that inhibits the dimerization of the protease. A focused, structure-based library of inhibitors was designed for the Phe1i and Phe5i positions of a minimal pharmacophore to improve the potency of the dimerization inhibition through optimization of hydrophobic interactions. 4,4′-Biphenylalanine and thyroxine mutants at Phe1i position were highly exhibited a 13- and 42-fold increase in inhibition, respectively. The same minimal pharmacophore was also used in the design of covalent reversible inhibitors. A total of 18 nitrile containing inhibitors were prepared, and these agents were found to inhibit the dimerization of HIV-1 protease. Although evidence for formation of the covalent thioimidate intermediate was not obtained under the reaction condition, several of the nitrile containing compounds demonstrated increased inhibitory potency. The importance of the hydrophobic interaction between the phenyl sidechain of the inhibitors and HIV-1 protease was demonstrated. Finally, a combinatorial methodology was successfully developed to generate a library of inhibitors containing a disulfide linkage in the tether with varying numbers of mutations. Screening of the library with immobilized HIV-1 protease Q7K was not successful due to nonspecific binding events. The source of the nonspecific binding was discussed and alternatives were proposed.

Degree

Ph.D.

Advisors

Chmielewski, Purdue University.

Subject Area

Organic chemistry|Biochemistry

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