Design, screening and biological evaluation of novel fatty acid chain-modified oxyntomodulin-based derivatives with prolonged glucose-lowering ability and potent anti-obesity effects

Organic & Biomolecular Chemistry
Lei ZhaoLixia Sun

Abstract

Recently, oxyntomodulin (OXM) has emerged as a treatment option for type 2 diabetes mellitus and obesity. In order to develop more promising novel OXM derivatives combining glycemic effects of glucagon-like peptide-1 (GLP-1) and lipolytic properties of glucagon, six 12-mer GLP-1 receptor agonists (PP01-PP06) were screened using a phage display method and then fused to OXM (3-37) to generate hybrid OXM derivatives (PP07-PP12). PP11, as a selected starting point, was further site-specifically modified with three lengths of fatty acid chains to provide long-acting conjugates PP13-PP24, among which PP18 was found not only to retain almost the entire balanced activation potency of PP11 in GLP-1/glucagon receptors but also to enhance plasma stability and prolong hypoglycemic activity. PP18 was further confirmed as an insulin secretagogue and glycemic agent in gene knockout mice. The protracted antidiabetic effects and in vivo half-life of PP18 were further proved by hypoglycemic efficacies in diet-induced obesity (DIO) mice and pharmacokinetics tests in Sprague Dawley (SD) rats, respectively. Nevertheless, administration of PP18 once per day normalized food intake, body weight, blood biochemical indexes, insulin resistance and islet ...Continue Reading

References

Mar 10, 1998·European Journal of Biochemistry·M PopkovR Mandeville
Nov 15, 2000·Methods in Enzymology·S S SidhuJ A Wells
Aug 14, 2001·Journal of Molecular Recognition : JMR·R L Rich, D G Myszka
Oct 15, 2003·The Journal of Clinical Endocrinology and Metabolism·Mark A CohenStephen R Bloom
Mar 6, 2004·Endocrinology·Catherine L DakinStephen R Bloom
Mar 7, 2006·Cell Metabolism·Daniel J Drucker
Apr 19, 2006·International Journal of Obesity : Journal of the International Association for the Study of Obesity·K WynneS R Bloom
Jul 15, 2009·Nature Chemical Biology·Jonathan W DayMatthias H Tschöp
Mar 17, 2010·The American Journal of Medicine·Anne Peters
Feb 5, 2011·Journal of Peptide Science : an Official Publication of the European Peptide Society·Alessia SantopreteAntonello Pessi
Jan 4, 2012·Diabetes Care·UNKNOWN American Diabetes Association
Apr 22, 2014·Molecular Metabolism·Alessandro Pocai
Jun 7, 2014·The Journal of Pharmacology and Experimental Therapeutics·Louise S DalbøgeKeld Fosgerau
Aug 27, 2015·Journal of Medicinal Chemistry·Jesper LauThomas Kruse
May 27, 2016·The Journal of Biological Chemistry·Li-Hua ZhaoH Eric Xu
Jul 15, 2016·Cell Metabolism·Matthias H TschöpRichard D DiMarchi
Feb 9, 2017·Frontiers in Endocrinology·Arun ChaudhuryWasique Mirza
Feb 24, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xia ZhongZhi Chen

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Methods Mentioned

BETA
phage display
six hybrid
acylation
PCR
ELISA
nuclear magnetic resonance

Software Mentioned

Biacore T200

Related Concepts

Related Feeds

Cardiovascular Biology of GLP-1

Glucagon-like peptide 1 (GLP-1) plays a role in glucose metabolism, energy homeostasis, and inflammation suppression. GLP-1 receptor signaling has been shown to impact cardiovascular function. This feed focuses on the role of GLP-1 and GLP-1 receptor agonists on cardiovascular biology.