Potent and selective photo-inactivation of proteins with peptoid-ruthenium conjugates

Ru(II)(tris-bipyridyl)2+ derivatives photocatalytically generate singlet oxygen. Attaching these ruthenium conjugates to small-molecule inhibitors of intracellular or integral membrane proteins turned modest-potency compounds into chemical knockout reagents that potently inactivated targets in response to light. Advances in high-throughput screening now enable the rapid discovery of bioactive small molecules, but these primary hits almost always exhibit modest potency. We report a strategy for the transformation of these hits into much more potent inhibitors without compound optimization. Appending a derivative of Ru(II)(tris-bipyridyl)2+, an efficient photosensitizer of singlet oxygen production, to synthetic protein-binding compounds results in highly potent and specific target protein inactivation upon irradiation with visible light.