Details

Autor(en) / Beteiligte

• Reed, Anthony B.
• Lanman, Brian A.
• Holder, Jerry Ryan
• Yang, Bryant H.
• Ma, Ji
• Humphreys, Sara C.
• Wang, Zhican
• Chan, Joyce C.Y.
• Miranda, Les P.
• Swaminath, Gayathri
• Allen, John G.

Titel

Half-life extension of peptidic APJ agonists by N-terminal lipid conjugation

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2020-11, Vol.30 (21), p.127499-127499, Article 127499

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2020

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• [Display omitted] •Lipidated apelin-13 showed in an increase in ejection fraction in an anesthetized rat myocardial infarction model.•Rat plasma protein binding of C13-lipidated apelin-13 was measured.•Rat PK (iv and sc) was measured for 15-mer peptide APJ agonists; half-life extension was observed for these peptides.•The length and type (fatty acid or lipid diacid) of lipid group affects the absorptive phase of subcutaneous dosing.•Lipidation increases plasma protein binding and extends the half-lives of peptides. Agonism of the endothelial receptor APJ (putative receptor protein related to AT1; AT1: angiotensin II receptor type 1) has the potential to ameliorate congestive heart failure by increasing cardiac output without inducing hypertrophy. Although the endogenous agonist, pyr-apelin-13 (1), has shown beneficial APJ-mediated inotropic effects in rats and humans, such effects are short-lived given its extremely short half-life. Here, we report the conjugation of 1 to a fatty acid, providing a lipidated peptide (2) with increased stability that retains inotropic activity in an anesthetized rat myocardial infarction (MI) model. We also report the preparation of a library of 15-mer APJ agonist peptide-lipid conjugates, including adipoyl-γGlu-OEG-OEG-hArg-r-Q-hArg-P-r-NMeLeuSHK-G-Oic-pIPhe-P-DBip-OH (17), a potent APJ agonist with high plasma protein binding and a half-life suitable for once-daily subcutaneous dosing in rats. A correlation between subcutaneous absorption rate and lipid length/type of these conjugates is also reported.