title: HIV protease-mediated activation of sterically capped proteasome inhibitors and substrates.
abstract: 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.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Buckley
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Corson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Aberle
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000818:Animals; D002417:Cattle; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors
chemical_list: D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D016333:HIV Protease; D046988:Proteasome Endopeptidase Complex