期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 20, 页码 12073-12082出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01395
关键词
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资金
- Canadian Institutes of Health Research (CIHR) [136921]
- Natural Sciences and Engineering Council of Canada (NSERC)
- Alberta Innovates Health Solutions (AIHS)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- College de France
Apelin is an important contributor to the renin-angiotensin axis, regulating cardiovascular, metabolic, and neurological functions. Apelin-17 has especially potent cardio-physiological effects but is rapidly degraded in human blood (t(0.5) similar to 18 h min). Angiotensin-converting enzyme 2 (ACE-2), neprilysin (NEP), and plasma kallikrein (KLKB1) cleave and inactivate it, with the latter cutting within the arginine-arginine site. Here, we show that analogues with an N-terminal polyethylene glycol (PEG) extension as well as peptide bond isosteres resist KLKB1 cleavage but that only the PEG-extended analogues significantly improve physiologically activity. The PEGylated analogues feature comparatively high log D-7(.4) values and high plasma protein binding, adding to their stability. An alanine scan of apelin-17 reveals that the integrity and conformational flexibility of the KFRR motif are necessary for cardio-physiological activity. An optimized Cbz-PEG(6) analogue is presented that is stable in blood (t(0.5) similar to 18 h), has significant blood-pressure lowering effect, and shows fast recovery of heart function in Langendorff assay.
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