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Thyroid hormone resistance: Mechanisms and therapeutic development
Benqiang Yao1, Chunyan Yang1, Chengxi Pan1
1The State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361005, China.
Thyroid hormone resistance (RTH) impairs hormone function, often due to TRβ mutations. New thyromimetic drugs show promise for RTH treatment by bypassing defective receptors, but require careful application.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Thyroid hormone (TH) is crucial for human growth, metabolism, and development.
- Thyroid hormone resistance (RTH) arises from impaired TH signaling, often due to mutations in thyroid hormone receptors (TRs).
- RTH affects target cell response to TH, leading to symptoms like goiter, developmental delays, and heart rate abnormalities.
Purpose of the Study:
- To review the structural mechanisms of RTH caused by TR mutations.
- To discuss therapeutic strategies for RTH, including the development of novel thyromimetic compounds.
- To highlight the importance of understanding TR structure-activity relationships for drug design.
Main Methods:
- Review of reported TRβ and TRα variants in RTH patients.
- Analysis of structure-activity relationship (SAR) studies for TH analogs.
- Discussion of drug design strategies targeting TRs.
Main Results:
- Over 170 TRβ and 20 TRα variants are linked to RTH.
- Thyroid hormone analogs can be designed to bypass defective TRs or transporters.
- Careful application of TH analogs is needed to avoid TRα overactivation and cardiac issues.
Conclusions:
- Understanding mutation-induced RTH mechanisms is key for therapeutic development.
- Novel thyromimetics offer potential RTH treatments by selectively targeting TRs.
- Further research is needed to optimize RTH therapies and minimize side effects.
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