Optimization of the structure of TTR Ligands for Half-life Extension (TLHE)

Author

Guanming Jiang, University of the PacificFollow

Date of Award

2022

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Mamoun M. Alhamadsheh

First Committee Member

Miki S. Park

Second Committee Member

Qinliang Zhao

Abstract

Many potential therapeutic agents face challenges for their clinical development due to short circulation half-life. As a result, prolonging the half-life of therapeutic drugs in circulation while preserving their hydrophilicity and small size will be a key step toward more effective and safe pharmacological molecules. Our lab developed a new approach for enhancing the safety and efficacy of therapeutic agents. By endowing therapeutic agents with a hydrophilic small molecule (a derivative of the clinical candidate, AG10) which reversibly binds to the serum protein transthyretin (TTR), the half-life of the therapeutic agent should be extended by binding to the TTR in serum. We termed this technology TTR Ligand for half-life extension (TLHEs). The approach involved using TLHE, which binds with TTR by high specificity and affinity. Our group has already shown that this technology extends the half-life of peptides, small molecules, and proteins without seriously affecting their binding activity towards their receptor and efficacy. As we are expanding the applicability of TLHE to extend the half-life of hydrophobic moieties, increasing the polarity of the TLHE linker could be beneficial to maintain overall hydrophilicity. Our main objective here is to see the effect of TTR binding affinity and selectivity of TLHE in serum when we attach a hydrophilic glutamic acid in the TLHE linker.

Pages

41

Recommended Citation

Jiang, Guanming. (2022). Optimization of the structure of TTR Ligands for Half-life Extension (TLHE). University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/3795