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ACS Med Chem Lett. 2019 Jul 5;10(8):1166-1172. doi: 10.1021/acsmedchemlett.9b00182. eCollection 2019 Aug 8.

Design of a Long-Acting and Selective MEG-Fatty Acid Stapled Prolactin-Releasing Peptide Analog.

Author information

1
Calibr at Scripps Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.

Abstract

Anorexigenic peptides offer promise as potential therapies targeting the escalating global obesity epidemic. Prolactin-releasing peptide (PrRP), a novel member of the RFamide family secreted by the hypothalamus, shows therapeutic potential by decreasing food intake and body weight in rodent models via GPR10 activation. Here we describe the design of a long-acting PrRP using our recently developed novel multiple ethylene glycol-fatty acid (MEG-FA) stapling platform. By incorporating serum albumin binding fatty acids onto a covalent side chain staple, we have generated a series of MEG-FA stapled PrRP analogs with enhanced serum stability and in vivo half-life. Our lead compound 18-S4 exhibits good in vitro potency and selectivity against GPR10, improved serum stability, and extended in vivo half-life (7.8 h) in mouse. Furthermore, 18-S4 demonstrates a potent body weight reduction effect in a diet-induced obesity (DIO) mouse model, representing a promising long-acting PrRP analog for further evaluation in the chronic obesity setting.

PMID:
31413801
PMCID:
PMC6691568
[Available on 2020-08-08]
DOI:
10.1021/acsmedchemlett.9b00182

Conflict of interest statement

The authors declare no competing financial interest.

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