Synthesis and biological properties of insulin-deoxycholic acid chemical conjugates

Seulki Lee, Kwangmeyung Kim, Tadiparthi Suresh Kumar, Jisook Lee, Kyoon Kim Sang, Yun Lee Dong, Yong Kyu Lee, Youngro Byun

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70 Citations (Scopus)

Abstract

Bile acids have been considered very useful in the preparation of new pharmaceuticals, and more recently in the preparation of peptide and protein drugs because of their natural chemical and biological properties. In this study, we modified recombinant human insulin by covalently attaching deoxycholic acid (DOCA) derivatives in order to synthesize orally active insulin analogues. DOCA derivatives, namely succinimido deoxycholate and succinimido bisdeoxycholyl-L-lysine were prepared and site specifically conjugated at LysB29 of insulin. The resultant insulin conjugates, [N B29-deoxycholyl] insulin (Ins-DOCA) and [NB29- bisdeoxycholyl-L-lysil] insulin (Ins-bisDOCA), were studied for their chemical, structural, and biological properties. Their chemical properties were determined by HPLC, MALDI-TOF mass spectroscopy, and dynamic light scattering. Lipophilicity and self-aggregation behavior of insulin conjugates were enhanced with increasing number of labeled bile acid. The far-ultraviolet region of circular dichroism spectra showed no significant change of the tertiary structure of insulin in aqueous solution due to conjugation. Competitive insulin binding assay with HepG2 cells revealed that monosubstituted insulin conjugates still retained high binding affinity to the insulin receptor. When the insulin conjugates were intravenously administered (0.33 IU/kg) to streptozotocin (STZ)-induced diabetic rats, the conjugates showed sustained biological activity for a longer period with the similar lowest blood glucose level (glucose nadir), compared to native insulin. In further studies, the resulting new insulin conjugates will be investigated for their oral efficiency as a long-acting insulin formulation for the treatment of diabetic patients.

Original languageEnglish
Pages (from-to)615-620
Number of pages6
JournalBioconjugate Chemistry
Volume16
Issue number3
DOIs
Publication statusPublished - 2005 May
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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    Lee, S., Kim, K., Kumar, T. S., Lee, J., Sang, K. K., Dong, Y. L., Lee, Y. K., & Byun, Y. (2005). Synthesis and biological properties of insulin-deoxycholic acid chemical conjugates. Bioconjugate Chemistry, 16(3), 615-620. https://doi.org/10.1021/bc049871e