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Engineering super-powered proteins for disease therapy

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Lei Wang

Enhanced proteins equipped with stable artificial amino acids, recently developed by Salk associate professor Lei Wang, are proving to be promising candidates for future therapeutic use, particularly in cancer.

Protein-based therapy could, in theory, directly target a variety of diseases and be less toxic than other drugs. However, attempts to engineer proteins with therapeutic characteristics by genetically integrating artificial amino acids have often failed, until recently.

"We can provide novel insights into mechanisms of some types of cancers and aim to eventually develop a really useful biologically based drug," says Wang, who is also the Frederick B. Rentschler Developmental Chair. "And we can certainly expand this new platform technology into multiple other areas, such as neurodegenerative diseases, immunology, stroke treatment and more."

Wang first outlined the breakthrough technology last summer, when he announced the development of an artificial amino acid that was able to genetically assimilate into a protein and provide strong bonds within the protein. The challenge was to develop an amino acid not too chemically active (and thereby likely to destroy the cell), but reactive enough to provide a new ability once in the protein.

The artificial amino acid Wang and his collaborators created— dubbed Ffact—meets this balance by forming an irreversible bond when near the naturally occurring Cys amino acid. This controlled bonding (called "proximity-enabled protein crosslinking," or PEPC) is like a s taple, letting researchers bind and shape proteins that can, for example, target cellular proteins thought to go astray in some cancers. Since Ffact, Wang and his lab have created about a dozen similarly effective amino acids for wielding fine control over the shape of the protein. He is aiming to build a library of about 50 for varied therapeutic tests.

These PEPC-capable amino acids promise to advance protein therapies in two important ways: by providing proteins with the ability to interact with other proteins and by beefing up their stability. "What we're doing is totally different from the traditional way of thinking," says Wang. "Previously, artificial amino acids were used as a probe or handle for tracking proteins. But now we are making the protein interact with native proteins as well as making itself stronger."

Now armed with the new amino acids, Wang's lab is configuring proteins to target and interact with pathways involved in cancer— most particularly, pathways that halt the cell's self-destruct sequence (apoptosis), leading to cancer's unchecked and deadly proliferation. The lab is currently focusing on types of proteins known to be involved in cancer's inhibition of apoptosis, such as p53, STAT and caspases. Wang says the results have been very interesting so far, and he looks forward to sharing them in the coming year.