by Michael Pennington
Appetite disorders are of major medical concern with a clear unmet need for improved therapies. Obesity has been termed a “worldwide epidemic” by the World Health Organization (WHO),1 and associated metabolic disorders such as diabetes mellitus cause significant morbidity and mortality. Conversely, the anorexia and cachexia of malignant and inflammatory disease also contribute significantly to the disease burden in affected patients. Currently used pharmacological interventions have limited utility or produce severe side effects.2 Bariatric surgery, for example, is the only treatment found to be effective for managing morbid obesity.3 In light of this, the gut endocrine system and the factors that control it, especially peptide hormones, are of huge interest.
Insulin-like peptide 5 (INSL5) was originally identified as a novel peptide hormone with high expression in the gut.4 Similar in structure to relaxin and insulin, it is a two chain molecule with both intra and intermolecular disulfide bonds. Subsequent studies identified its receptor as the G protein coupled receptor known as relaxin family peptide receptor 4 (RXFP4).5 The function of INSL5 acting through RXFP4 was unknown until recently when it was identified that INSL5 is a hormonal product of colonic L-cells that enhances food intake in mice.6 In line with the expected properties of an orexigenic hormone, INSL5 plasma levels and colonic mRNA transcripts were elevated by caloric restriction, and circulating INSL5 concentrations were suppressed by refeeding.6 Knockout of the receptor RXFP4, or treatment with antibodies against endogenous INSL5, reduced refeeding responses after fasting.6 These data strongly suggest that INSL5 is an orexigenic hormone that plays a physiological role in driving food intake. Thus, RXFP4 is a novel drug target and an agonist might be of potential therapeutic for the treatment of anorexia.
In a recent report from Patil, et al., from the Wade lab at the Florey Institute in Australia (http://www.ncbi.nlm.nih.gov/pubmed/26824523 ), a series of human and mouse INSL5 (hINSL5/mINSL5) analogues were designed and chemically synthesized, resulting in a chimeric INSL5 analogue exhibiting more than 10-fold higher potency (0.35 nM) at human RXFP4 compared with native hINSL5 (4.57 nM). The SAR study also identified a key residue (KA15) in the A-chain of mINSL5 that contributes to improved RXFP4 affinity and potency of mINSL5 compared with hINSL5. This knowledge ultimately led to engineering a minimized hINSL5 mimetic agonist that retains native hINSL5-like RXFP4 affinity and potency at human RXFP4. This minimized analogue was synthesized in 17.5-fold higher yield and in less time compared with hINSL5.
- Caballero, B. The global epidemic of obesity: An overview. Epidemiol. Rev. 2007, 29, 1−5.
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- Schigt, A.; Gerdes, V. E.; Cense, H. A.; Berends, F. J.; van Dielen, F. M.; Janssen, I.; van der Laar, A.; van Wagensveld, B. A.; Romijn, J. A.; Serlie, M. J. Bariatric surgery is an effective treatment for morbid obesity. Neth. J. Med. 2013, 71 (1), 4−9.
- Conklin, D.; Lofton-Day, C. E.; Haldeman, B. A.; Ching, A.; Whitmore, T. E.; Lok, S.; Jaspers, S. Identification of INSL5, a new member of the insulin superfamily. Genomics 1999, 60, 50−56.
- Liu, C.; Kuei, C.; Sutton, S.; Chen, J.; Bonaventure, P.; Wu, J.; Nepomuceno, D.; Kamme, F.; Tran, D. T.; Zhu, J.; Wilkinson, T.; Bathgate, R.; Eriste, E.; Sillard, R.; Lovenberg, T. W. INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J. Biol. Chem. 2005, 280, 292−300.
- Grosse, J.; Heffron, H.; Burling, K.; Hossain, M. A.; Habib, A. M.; Rogers, G. J.; Richards, P.; Larder, R.; Rimmington, D.; Adriaenssens,A. A.; Parton, L.; Powell, J.; Binda, M.; Colledge, W. H.; Doran, J.;Toyoda, Y.; Wade, J. D.; Aparicio, S.; Carlton, M. B.; Coll, A. P.; Reimann, F.; O’Rahilly, S.; Gribble, F. M. Insulin-like peptide 5 is anorexigenic gastrointestinal hormone. Proc. Natl. Acad. Sci. U. S. A.
2014, 111, 11133−11138.