Agents have been designed and synthesized which target
the dimerization interface of HIV-1 protease.
These agents, which contain cross-linked peptides from the N- and
C-termini of the protease, both inhibit HIV-1
protease activity and decrease the amount of protease dimer in solution
as measured by size exclusion chromatography,
protein crosslinking, and protease fluorescence studies.
Additionally we have shown that active site-targeted
agents
inhibit HIV-1 protease activity but have little effect on protease
dimerization. These data support the claim that
inhibition with the crosslinked agents is based on a decrease in the
amount of protease homodimer in solution which
in turn is responsible for a decrease in the activity of the
protease.
Disrupting protein-protein interactions in multi-subunit enzymes is currently an underutilized mode of inhibition, and little information exists to assist the researcher in the design of agents to effect such a change within the enzyme. This work seeks to address these limitations by providing a general strategy for the design of dimerization inhibitors of the therapeutically significant enzyme HIV-1 protease.
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