Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis

Authors

Mark Miller, University of the Pacific
Arindom Pal, University of the Pacific
Wabel Albusairi, University of the Pacific
Hyun Joo, University of the PacificFollow
Beverly Pappas, University of the Pacific
Tariqul Haque Tuhin, University of the Pacific
Dengpan Liang, University of the Pacific
Raghavendra Jampala, University of the Pacific
Fang Liu, University of the Pacific
Jared Khan, University of the Pacific
Marjon Faaij, University of the Pacific
Miki S. Park, University of the PacificFollow
William K. Chan, University of the PacificFollow
Isabella Graef, Stanford University
Robert Zamboni, Eidos Therapeutics
Neil Kumar, Eidos Therapeutics
Jonathan Fox, Eidos Therapeutics
Uma Sinha, Eidos Therapeutics
Mamoun Alhamadsheh, University of the PacificFollow

Document Type

Article

Publication Title

Journal of Medicinal Chemistry

ISSN

1520-4804

Volume

61

Issue

17

DOI

10.1021/acs.jmedchem.8b00817

First Page

7862

Last Page

7876

Publication Date

9-13-2018

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.

Recommended Citation

Miller, M., Pal, A., Albusairi, W., Joo, H., Pappas, B., Haque Tuhin, T., Liang, D., Jampala, R., Liu, F., Khan, J., Faaij, M., Park, M. S., Chan, W. K., Graef, I., Zamboni, R., Kumar, N., Fox, J., Sinha, U., & Alhamadsheh, M. (2018). Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis. Journal of Medicinal Chemistry, 61(17), 7862–7876. DOI: 10.1021/acs.jmedchem.8b00817
https://scholarlycommons.pacific.edu/phs-facarticles/395