Design and Synthesis of Potent, Long-Acting Lipidated Relaxin-2 Analogs

  • Bioconjug Chem. 2019 Jan 16;30(1):83-89. doi: 10.1021/acs.bioconjchem.8b00764.
Avinash Muppidi  1 ,  Sang Jun Lee  1 ,  Che-Hsiung Hsu  1 ,  Huafei Zou  1 ,  Candy Lee  1 ,  Elsa Pflimlin  1 ,  Madhupriya Mahankali  1 ,  Pengyu Yang  1 ,  Elizabeth Chao  1 ,  Insha Ahmad  1 ,  Andreas Crameri  1 ,  Danling Wang  1 ,  Ashley Woods  1 ,  Weijun Shen  1
Affiliations
  • 1. Calibr at the Scripps Research Institute , 11119 North Torrey Pines Road , La Jolla , California 92037 , United States.
PMID: 30543420 DOI: 10.1021/acs.bioconjchem.8b00764
Abstract

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 vivo half-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.

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