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May 07, 2012
 |  BioCentury  |  Emerging Company Profile

Principia: Reversing covalency

Principia developing reversible inhibitors for cancer, autoimmune diseases

Principia Biopharma Inc. is developing a pipeline of small molecule reversible covalent inhibitors it is betting will have fewer off-target effects and lower immunogenicity than irreversible inhibitors.

The company is using its chemistry technology to add a reactive cyanoacrylamide group to small molecules. The group forms a reversible covalent bond with an exposed cysteine residue in the active site of a target protein. When the protein denatures, the inhibitor falls off.

In contrast, irreversible inhibitors remain bound to the protein and create permanent adducts that may be recognized by the immune system as foreign, leading to inflammation and autoimmunity.

Importantly, the temporary covalent bond means the inhibitor also will fall off if it binds to the wrong protein. By comparison, an irreversible covalent inhibitor remains permanently bound to the incorrect protein, which can lead to sustained off-target effects.

According to CEO Martin Babler, most irreversible covalent inhibitors are being developed for cancer because the off-target...

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