Design, synthesis and preclinical evaluation of bio-conjugated amylinomimetic peptides as long-acting amylin receptor agonists

Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administr...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2022-06, Vol.236, p.114330-114330, Article 114330
Main Authors: Patch, Raymond J., Zhang, Rui, Edavettal, Suzanne, Macielag, Mark J., Eckardt, Annette J., Li, Jiali, Rives, Marie-Laure, Edwards, Wilson, Hinke, Simon A., Qiu, Xi, Jian, Wenying, Libiger, Ondrej, Zheng, Songmao, Jeyaseelan, Jey, Liang, Yin, Rangwala, Shamina M., Leonard, James N., Hornby, Pamela
Format: Article
Language:English
Subjects:
Amylin
Bioconjugate
Food intake
Obesity
Pramlintide
Satiety
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Summary:Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic thioether motif. This modification enabled stable chemical conjugation to a half-life extending antibody. In contrast to pramlintide (t1/2 
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114330