Synthesis of AG10 analogs and optimization of TTR ligands for Half-life enhancement (TLHE) of Peptides
The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidosis, which is most commonly, caused by aggregation of Immunoglobulin (Ig) light chains or transthyretin (TTR) in the cardiac muscle, represen...
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| Format: | Others |
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Scholarly Commons
2017
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| Online Access: | https://scholarlycommons.pacific.edu/uop_etds/2975 https://scholarlycommons.pacific.edu/cgi/viewcontent.cgi?article=3974&context=uop_etds |
| Summary: | The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidosis, which is most commonly, caused by aggregation of Immunoglobulin (Ig) light chains or transthyretin (TTR) in the cardiac muscle, represent an important and often underdiagnosed cause of heart failure. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. AG10 is a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of TTR in serum samples obtained from patients with amyloid cardiomyopathy. The oral bioavailability and selectivity of AG10, makes it a very promising candidate to treat TTR amyloid cardiomyopathy. Understanding the reason behind the potency of AG10 would be beneficial for designing stabilizers for other amyloid diseases. This would be possible by designing and synthesizing structural analogues of AG10. Here we report the synthesis, characterization and analysis of AG10 analogs and the comparison of the in vitro activities of the synthesized analogs.
The tremendous therapeutic potential of peptides has not been fulfilled and potential peptide therapies that have failed far outnumber the successes so far. A major challenge impeding the more widespread use of peptides as therapeutics is their poor pharmacokinetic profile, due to short In vivo half-life resulting from inactivation by serum proteases and rapid elimination by kidneys. Extending the In vivo half-life of peptides is clearly desirable in order for their therapeutic potential to be realized, without the need for high doses and/or frequent administration. Covalent conjugation of peptides to macromolecules (e.g. polyethylene glycol or serum proteins such albumin) has been the mainstay approach for enhancing the In vivo half-life of peptides. However, the steric hindrance and immunogenicity of these large macromolecules often compromises the In vivo efficacy of the peptides. Recently, our laboratory established the first successful reversible method of extending the half-life of peptides using serum protein TTR. The approach involved the use of a TTR Ligand for Half-life Extension (TLHE-1) which binds to TTR with high specificity and affinity. We have shown that our technology extends the half-life of multiple peptides without seriously affecting their activity. Our main objective here is to modify the structure of TLHE1 using linkers with different length and composition to optimize its affinity and selectivity for TTR in human serum. |
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