Tagged for Destruction

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Science  22 Jul 2011:
Vol. 333, Issue 6041, pp. 387
DOI: 10.1126/science.333.6041.387-c

Promising new drug targets have come from deep sequencing, microarray studies, and genome-wide RNA interference screens; however, validation of these potential targets by specific in vivo inhibition remains a challenge. Neklesa et al. describe a new technology to address this problem that takes advantage of the fact that exposure of hydrophobic regions induces cellular stress and targets proteins for destruction by the proteasome. The strategy makes use of an existing technology: the introduction of a single fusion domain, the HaloTag protein (a bacterial dehalogenase), to the target protein. The HaloTag includes a reactive linker, which, when bound to a hydrophobic compound, induces protein degradation. The authors designed and synthesized hydrophobic small molecules to bind the HaloTag protein. On the basis of initial testing, the authors chose an adamantyl compound, HyT13, which was potent and nontoxic. In other destabilization-domain–based systems, a ligand has to be provided to prevent destabilization. The HaloTag-HyT13 system has the advantage that compound administration induces degradation. Proof-of-principle experiments showed degradation of a protein expressed in zebrafish embryos and of an oncogenic protein in cell culture and in mice.

Nat. Chem. Biol. 7, 10.1038/nchembio.597 (2011).

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