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New Chemical Genetic tool forces cells to target and destroy harmful proteins within those cells

Yale University : 11 April, 2003  (New Product)
When 'rogue' proteins begin wreaking havoc within cells, the result is diseases such as cancer, heart disease, and inflammatory diseases like rheumatoid arthritis.
Scientists at Yale University and the Howard Hughes Medical Institute at California Institute of Technology have created a new technology to push the out-of-control protein into closer proximity of the cell's natural protein degradatory machinery.

'We hijack the cell's protein degradatory machine for our purposes and induce the destruction of the protein whether the cells wants it degraded or not,' said Craig Crews, associate professor of pharmacology and of molecular, cellular and developmental biology at Yale School of Medicine. He and Cal Tech collaborator Ray Deshaies believe the technology has enormous therapeutic and screening potential.

Speaking at the Experimental Biology 2003 meeting in San Diego on Tuesday, Crews will present the first evidence that the new technology, called Protacs, works as hoped within intact cells. Protacs is shorthand for Proteolysis Targeting Chimera. Earlier studies at Yale and Cal Tech had demonstrated Protac's success in targeting and destroying proteins in a cell-free assay.

The Protacs system, developed by Crews in collaboration with Deshaies, is a carefully constructed chimeric compound. It uses components of the ubiquination pathway, a naturally-occurring pathway of enzymes and ligases, that degrade cellular proteins as required for normal maintenance of cellular function. By adding recruiting given proteins to specific types of ubiquitin-protein ligases, the team was able to target these proteins for destruction.

In the study reported at the meeting, Crews first introduced a green fluorescent protein fused with a small molecule receptor into cells grown in a petri dish. Simply adding a Protac molecule to the cell culture, the green fluorescent protein fusion protein was induced in order to be degraded. This was possible because the Protac molecule is a dumbbell-shaped compound. On one end, a chemical binds to the green fluorescent protein. On the other end a different chemical binds to a ubiquitin ligase. Thus, by binding both target protein and the ubiquitin-mediated protein degradation machinery, Protacs recruit proteins for their untimely demise. In the case of the proof-of-concept experiment performed by Crews' laboratory, the protein degradation was readily observed as the green fluorescent protein degraded and the cells lost fluorescence within an hour.

Crews said these results suggest Protacs has enormous potential as a therapeutic tool to degrade or destroy the proteins causing problems, in the same way that genetic therapy attempts to change or stop the function of a particular protein by altering the DNA encoding that protein.

With the development of a library of Protacs compounds, Protacs also could be used to perform large-scale chemical genetic screens of protein loss of function.
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