Peptides. 102():8–15, APR 2018

DOI: 10.1016/j.peptides.2018.01.014

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PMID: 29391187

Issn Print: 0196-9781

Publication Date: 2018/04/01


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Discovery of a long-acting glucagon-like peptide-1 analog with enhanced aggregation propensity

Mitsuaki Takeuchi;Masayuki Okamoto;Ryuji Okamoto;Hiroshi Kinoshita;Yu Yamaguchi;Nobuhide Watanabe;

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Abstract

HIGHLIGHTS[Ser8]-GLP-1(7–35)-GVKALIDEILAA-NH2 was found as a new long-acting GLP-1 analog.Our experiments suggest that this GLP-1 analog remains oligomeric in the circulation.The newly discovered GLP-1 analog has potent long-acting therapeutic effects in diabetic mice.In the course of our search for new GLP-1 analogs, we screened a number of [Ser8]-GLP-1 analogs using the C-terminal helix 3 of the albumin binding domain 3 of protein G from bacterial Streptococcal G strain 148 (G148-ABD3) as appendage. Our efforts led to the discovery of [Ser8]-GLP-1 (7–35)-GVKALIDEILAA-NH2, peptide 6, as a long-acting GLP-1 analog with enhanced self-associated aggregation. Peptide 6 showed enhanced stability in rat and human plasma and an extended half-life of 5.4h with good bioavailability in rats and subsequently prolonged therapeutic effects in diabetic mice. Analytical ultracentrifugation and TLC suggest that 6 remains oligomeric in the circulation, which accounts for its extended in vivo half-life. The present work shows the possible enhancement of medium-sized oligopeptides aggregation propensity and highlights the potential advantages of peptide aggregates for long-acting peptide drugs.

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