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J Am Chem Soc. 2011 Feb 2;133(4):698-700. doi: 10.1021/ja109377p.

HIV protease-mediated activation of sterically capped proteasome inhibitors and substrates.

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Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.


Strategies for selectively killing HIV-infected cells present an appealing alternative to traditional antiretroviral drugs. We show here the first example of an inactive “Trojan horse” molecule that releases a cytotoxic, small-molecule proteasome inhibitor upon cleavage by HIV-1 protease. As a proof-of-concept strategy, the protein avidin was used to block entry of the compound into the proteasome in the absence of HIV-1 protease. We demonstrate that this strategy is also feasible without requiring an exogenous protein; a polylysine dendrimer-containing molecule is unable to enter the proteasome until cleaved by HIV-1 protease. These results demonstrate that conditional proteasome inhibitors could prove useful in the development of new tools for chemical biology and future therapeutics.

[Indexed for MEDLINE]

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