Aqueous-Soluble, Non-Reversible Lipid Conjugate of Salmon Calcitonin: Synthesis, Characterization and In Vivo Activity

Abstract

A novel non-reversible, water-soluble lipid conjugate of sCT was successfully synthesized that showed (1) different aggregation behavior and secondary structure, (2) improved enzymatic stability and cellular uptake, and (3) comparable hypocalcemic activity in vivo compared to sCT.

Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials

“…This strategy can insert more hydrophobic amino acids within the peptide backbone [95]. Additionally, improved protection against liver enzyme degradation was demonstrated for a lipidated peptide without loss in biological activity [96] or by reversible/non-reversible conjugation with lipophilic structures that can enhance the transcellular uptake [97,98].…”

Structural Modification of Proteins and Peptides

“…Cheng et al produced the analog, Mal-sCT water-soluble (-maleimido lysine derivative of palmitic acid) of salmon calcitonin, a 32-amino acid peptide drug by lipid modification. 41 It was found to have greater stability in-vivo with no compromise in the activity of the peptide. Disadvantages of this technique are that a lipid and a polypeptide are usually incompatible in reaction media, a directly linked lipid-polypeptide conjugate is very likely insoluble in water and lipidized polypeptides in general are of low biological activity.…”

Synthesis, Characterization and In Vivo Activity of Salmon Calcitonin Coconjugated With Lipid and Polyethylene Glycol

“…Mal-sCT was also more resistant than sCT to degradation in hepatic and intestinal milieu, but the level of enhanced stability was inadequate to allow Mal-sCT to be administered orally. 7 We hypothesized that PEGylation of Mal-sCT might not only sufficiently increase its stability to enzymatic degradation, but that the PEGylated lipidized sCT, through its aggregation into nanoparticles, might also have higher permeability across absorptive epithelia as has been demonstrated with the PCL-b-PEO nanoparticles. 4 To test the hypothesis that PEGylation was advantageous for Mal-sCT, this article set out to evaluate the synthesis, characterization and pharmacological activity of sCT coconjugated with lipid and PEG.…”

“…Rather, the lipid conjugation had promoted peptide stability in liver extract and peptide association with cell membrane. 7 Studies conducted in other laboratories have shown PEGmodification of sCT at Lys 18 to enhance its oral 9 and nasal 10 bioactivity by approximately three-to sixfold. While lipid modification of sCT at Lys 11 and Lys 18 did not affect its in vitro activity.…”

“…7 Mal-sCT consisted of sCT conjugated at Cys 1 and Cys 7 via thio-ether bonds with a pair of water-soluble emaleimido lysine derivative of palmitic acid. This peptide self-aggregated in aqueous media and was capable of producing comparable hypocalcemic activity to sCT in the rat model.…”