1. Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis
- Author
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Isabella A. Graef, Jonathan Fox, Mark Miller, Miki S. Park, Arindom Pal, Jared Khan, William K. Chan, Uma Sinha, Hyun Joo, Mamoun M. Alhamadsheh, Wabel Albusairi, Dengpan Liang, Fang Liu, Neil Kumar, Raghavendra Jampala, Robert Zamboni, Beverly Pappas, Tariqul Haque Tuhin, and Marjon Faaij
- Subjects
Male ,Models, Molecular ,0301 basic medicine ,endocrine system ,Protein Conformation ,Entropy ,Administration, Oral ,Serum Albumin, Human ,030204 cardiovascular system & hematology ,Benzoates ,Article ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Biomimetics ,Drug Discovery ,medicine ,Animals ,Humans ,Prealbumin ,Amyloid Neuropathies, Familial ,Molecular interactions ,biology ,Protein Stability ,Chemistry ,Amyloidosis ,Genetic variants ,nutritional and metabolic diseases ,medicine.disease ,Transthyretin ,030104 developmental biology ,Biochemistry ,Mutation ,biology.protein ,Pyrazoles ,Thermodynamics ,Molecular Medicine ,Fatal disease ,Female ,Amyloid cardiomyopathy - Abstract
Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading TTR stabilizers in clinic and structural features important for effective TTR stabilization is lacking. Here, we found that molecular interactions reflected in better binding enthalpy may be critical for development of TTR stabilizers with improved potency and selectivity. Our studies provide mechanistic insights into the unique binding mode of the TTR stabilizer, AG10, which could be attributed to mimicking the stabilizing T119M variant. Because of the lack of animal models for ATTR-CM, we developed an in vivo system in dogs which proved appropriate for assessing the pharmacokinetics-pharmacodynamics profile of TTR stabilizers. In addition to stabilizing TTR, we hypothesize that optimizing the binding enthalpy could have implications for designing therapeutic agents for other amyloid diseases.
- Published
- 2018