Novel Strategy To Inhibit Transthyretin Amyloidosis via the Synergetic Effect of Chemoselective Acylation and Noncovalent Inhibitor Release.

Abstract

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 T4 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.

• Authors: Seok Beom Lee, Jaeni Yu, Hyunwoo Kim, Kun Woo Kim, Jong Woo Jeong, Yun Lan Kim, Sung Jean Park, Tae-Sung Koo, Changwook Lee, Ki Bum Hong, Sungwook Choi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 4 Pg. 2893-2903 (02 23 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 36749109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prealbumin

Topics

• Humans
• Models, Molecular
• Amyloid Neuropathies, Familial (drug therapy)
• Binding Sites
• Drug Discovery
• Prealbumin (metabolism)