Mol Pharm 2017 Nov 06;1411:3954-3967. doi: 10.1021/acs.molpharmaceut.7b00632.

Micellar Nanomedicine of Novel Fatty Acid Modified Xenopus Glucagon-like Peptide-1: Improved Physicochemical Characteristics and Therapeutic Utilities for Type 2 Diabetes.

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To develop novel long-acting antidiabetics with improved therapeutic efficacy, two glucagon-like peptide-1 (GLP-1) analogs were constructed through the hybridization of key sequences of GLP-1, xenGLP-1B, exendin-4, and lixisenatide. Hybrids 1 and 2 demonstrated enhanced in vitro and in vivo biological activities and were further site-specifically lipidized at lysine residues to achieve prolonged duration of action and less frequent administration. Compared with their native peptides, compounds 3-6 showed similar in vitro activities but impaired in vivo acute hypoglycemic potencies due to decreased aqueous solubility and retarded absorption in vivo. To circumvent these issues, compound 3 (xenoglutide) was selected to be self-associated with sterically stabilized micelles (SSM). The α-helix and solubility of xenoglutide were significantly improved after self-associated with SSM. Notably, the improved physicochemical characteristics of xenoglutide-SSM led to revival of acute hypoglycemic ability without affecting its long-term glucose-lowering activity. Most importantly, preclinical studies demonstrated improved therapeutic effects and safety of xenoglutide-SSM in diabetic db/db mice. Our work suggests the SSM incorporation as an effective approach to improve the pharmacokinetic and biological properties of hydrophobicity peptide drugs. Furthermore, our data clearly indicate xenoglutide-SSM as a novel nanomedicine for the treatment of type 2 diabetics.

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Species referenced: Xenopus
Genes referenced: gcg

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