Dimerization inhibition of HIV -1 protease
Abstract
A novel strategy was developed for inhibiting HIV-1 protease based on the interactions between the two monomer units at the dimerization interface. The strategy involved inhibiting HIV-1 protease by disrupting the assembly of the dimer essential for activity. Peptides based on the residues present at the dimeric interface were crosslinked at their N-terminus by methylene units of varying lengths using a solid phase approach. The activity of these designed agents as inhibitors was evaluated. The agents were found to be reasonably potent with IC50 values in the low μM range. The role of aromatic residues in the inhibitors was further investigated by deletion and homologous mutagenesis. The mode of inhibition of HIV-1 protease by the inhibitors was analyzed by fluorescence, crosslinking experiments and size exclusion chromatography and was shown to be by interference with the dimerization process. Based on these dimerization inhibitors, irreversible inhibitors were designed to either target Cys 95 at the dimerization interface or to be photoactivatable.
Degree
Ph.D.
Advisors
Chmielewski, Purdue University.
Subject Area
Organic chemistry|Biochemistry|Immunology
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