Better Binding Through Chemistry

HHMI and Stanford scientists chose as their drug target a basic protein molecular subunit known as an "SH2 domain," which mediates protein-protein interactions that cause some diseases. This domain is regarded as a choice target for drug development because it is found in tyrosine kinases, enzymes that are critical components of the molecular machinery involved in cancer, osteoporosis, and inflammation. Despite its high profile among rational drug designers at pharmaceutical companies, the SH2 domain has proven to be an intractable drug target.

As their drug candidates, Crabtree and his colleagues chose peptides that contained the amino acid phosphotyrosine, which bind to the SH2 domain. The researchers hooked these peptides to a small linker molecule that sticks tightly to a human protein, FKBP.

Experiments with numerous peptide-linker combinations showed that certain combinations bound to the SH2 domain up to three times more tightly than did the peptide alone. These studies also demonstrated that it was possible to optimize binding by adjusting the linker segment so that it would place FKBP at just the right angle to produce the best fit with the target protein.

Medicinal chemists already take advantage of the fact that many drugs bind to blood-borne proteins such as serum albumin, which thereby allows small molecules to remain in circulation far longer than normal. Now, there is the potential to use another set of proteins to improve a drug's ability to bind to its target. "There are a great many candidate presenting proteins that exist inside and outside the cell, offering a wide variety of options for drug designers," says Crabtree.


Contact: Jim Keeley
Howard Hughes Medical Institute

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