Novel Strategy To Inhibit Transthyretin Amyloidosis via the Synergetic Effect of Chemoselective Acylation and Noncovalent Inhibitor Release.
Seok Beom LeeJaeni YuHyunwoo KimKun Woo KimJong Woo JeongYun Lan KimSung Jean ParkTae-Sung KooChangwook LeeKi Bum HongSungwook ChoiPublished in: Journal of medicinal chemistry (2023)
Strategies for developing targeted covalent inhibitors (TCIs), which have the advantages of a prolonged duration of action and selectivity toward a drug target, have attracted great interest in drug discovery. Herein, we report chemoselective covalent inhibitors that specifically target lysine ε-amine groups that conjugate with an endogenous protein to prevent disease-causing protein misfolding and aggregation. These TCIs are unique because the benzoyl group is preferentially conjugated to Lys15 at the top of the T 4 binding site within transthyretin (TTR) while simultaneously releasing a potent noncovalent TTR kinetic stabilizer. The potency of these covalent inhibitors is superior to tafamidis, the only FDA-approved drug for the treatment of hereditary TTR amyloidosis. In addition to investigations into the covalent modification of TTR via reverse-phase high-performance liquid chromatography, direct methods are performed to confirm and visualize the presumed covalent interaction via mass spectrometry and X-ray crystallography.
Keyphrases
- high performance liquid chromatography
- mass spectrometry
- drug discovery
- tandem mass spectrometry
- high resolution
- simultaneous determination
- amino acid
- cancer therapy
- liquid chromatography
- protein protein
- emergency department
- solid phase extraction
- binding protein
- magnetic resonance imaging
- multiple myeloma
- gas chromatography
- combination therapy
- drug administration
- dual energy