| Autor: |
Muppidi, Avinash, Lee, Sang Jun, Hsu, Che-Hsiung, Zou, Huafei, Lee, Candy, Pflimlin, Elsa, Mahankali, Madhupriya, Yang, Pengyu, Chao, Elizabeth, Ahmad, Insha, Crameri, Andreas, Wang, Danling, Woods, Ashley, Shen, Weijun |
| Zdroj: |
Bioconjugate Chemistry; December 2018, Vol. 30 Issue: 1 p83-89, 7p |
| Abstrakt: |
Peptide hormone relaxin-2, a member of the insulin family of peptides, plays a key role in hemodynamics and renal function and has shown preclinical efficacy in multiple disease models, including acute heart failure, fibrosis, preeclampsia, and corneal wound healing. Recently, serelaxin, a recombinant version of relaxin-2, has been studied in a large phase 3 clinical trial (RELAX-AHF-2) for acute decompensated heart failure patients with disappointing outcome. The poor in vivohalf-life of relaxin-2 may have limited its therapeutic efficacy and long-term cardiovascular benefit. Herein, we have developed a semisynthetic methodology and generated potent, fatty acid-conjugated relaxin analogs with long-acting pharmacokinetic (PK) profile in rodents. The enhanced PK properties translated into improved and long-lasting pharmacodynamic effect in pubic ligament elongation (PLE) studies. The resultant novel relaxin analog, R9-13, represents the first long-acting relaxin-2 analog and could potentially improve the clinical efficacy and outcome for this important peptide hormone. This semisynthetic methodology could also be applied to other cysteine-rich peptides and proteins for half-life extension. |
| Databáze: |
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