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Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control.

Publication ,  Journal Article
Amiram, M; Luginbuhl, KM; Li, X; Feinglos, MN; Chilkoti, A
Published in: Proceedings of the National Academy of Sciences of the United States of America
February 2013

Peptide drugs are an exciting class of pharmaceuticals increasingly used for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections and an undesirable "peak-and-valley" pharmacokinetic profile, which can cause undesirable side-effects. Synthetic prolonged release formulations can provide extended release of biologically active native peptide, but their synthetic nature can be an obstacle to production and utilization. Motivated by these limitations, we have developed a new and entirely genetically encoded peptide delivery system--Protease Operated Depots (PODs)--to provide sustained and tunable release of a peptide drug from an injectable s.c. depot. We demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes drug, and a thermally responsive, depot-forming elastin-like-polypeptide that undergoes a thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. We constructed synthetic genes for glucagon-like peptide-1 PODs and demonstrated their high-yield expression in Escherichia coli and facile purification by a nonchromatographic scheme we had previously developed. Remarkably, a single injection of glucagon-like peptide-1 PODs was able to reduce blood glucose levels in mice for up to 5 d, 120 times longer than an injection of the native peptide drug. These findings demonstrate that PODs provide the first genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

February 2013

Volume

110

Issue

8

Start / End Page

2792 / 2797

Related Subject Headings

  • Spectroscopy, Near-Infrared
  • Spectrometry, Fluorescence
  • Peptide Hydrolases
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Glucagon-Like Peptide 1
  • Blood Glucose
  • Animals
 

Citation

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Amiram, M., Luginbuhl, K. M., Li, X., Feinglos, M. N., & Chilkoti, A. (2013). Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control. Proceedings of the National Academy of Sciences of the United States of America, 110(8), 2792–2797. https://doi.org/10.1073/pnas.1214518110
Amiram, Miriam, Kelli M. Luginbuhl, Xinghai Li, Mark N. Feinglos, and Ashutosh Chilkoti. “Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control.Proceedings of the National Academy of Sciences of the United States of America 110, no. 8 (February 2013): 2792–97. https://doi.org/10.1073/pnas.1214518110.
Amiram M, Luginbuhl KM, Li X, Feinglos MN, Chilkoti A. Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control. Proceedings of the National Academy of Sciences of the United States of America. 2013 Feb;110(8):2792–7.
Amiram, Miriam, et al. “Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control.Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 8, Feb. 2013, pp. 2792–97. Epmc, doi:10.1073/pnas.1214518110.
Amiram M, Luginbuhl KM, Li X, Feinglos MN, Chilkoti A. Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control. Proceedings of the National Academy of Sciences of the United States of America. 2013 Feb;110(8):2792–2797.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

February 2013

Volume

110

Issue

8

Start / End Page

2792 / 2797

Related Subject Headings

  • Spectroscopy, Near-Infrared
  • Spectrometry, Fluorescence
  • Peptide Hydrolases
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Glucagon-Like Peptide 1
  • Blood Glucose
  • Animals