Apelin peptides linked to anti-serum albumin domain antibodies retain affinity in vitro and are efficacious receptor agonists in vivo
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The apelin receptor is a potential target in the treatment of heart failure and pulmonary arterial hypertension where levels of endogenous apelin peptides are reduced but significant receptor levels remain. Our aim was to characterise the pharmacology of a modified peptide agonist, MM202, designed to have high affinity for the apelin receptor and resistance to peptidase degradation and linked to an anti-serum albumin domain antibody (AlbudAb) to extend half-life in the blood. In competition binding experiments in human heart MM202-AlbudAb (pKi =9.39±0.09) bound with similar high affinity as the endogenous peptides [Pyr1 ]apelin-13 (pKi =8.83±0.06) and apelin-17 (pKi =9.57±0.08). [Pyr1 ]apelin-13 was 10-fold more potent in the cAMP (pD2 =9.52±0.05) compared to the β-arrestin (pD2 =8.53±0.03) assay, whereas apelin-17 (pD2 =10.31±0.28; pD2 =10.15±0.13, respectively) and MM202-AlbudAb (pD2 =9.15±0.12; pD2 =9.26±0.03, respectively) were equipotent in both assays, with MM202-AlbudAb 10-fold less potent than apelin-17. MM202-AlbudAb bound to immobilised human serum albumin with high affinity (pKD =9.02). In anaesthetised, male Sprague-Dawley rats, MM202-AlbudAb (5nmol, n=15) significantly reduced left ventricular systolic pressure by 6.61±1.46mmHg and systolic arterial pressure by 14.12±3.35mmHg and significantly increased cardiac contractility by 533±170mmHg/s, cardiac output by 1277±190RVU/min, stroke volume by 3.09±0.47RVU and heart rate by 4.64±2.24BPM. This study demonstrates that conjugating an apelin mimetic peptide to the AlbudAb structure retains receptor and in vivo activity and may be a new strategy for development of apelin peptides as therapeutic agents.
Date Issued
2020-06
Date Acceptance
2019-03-14
Citation
Basic and Clinical Pharmacology and Toxicology, 2020, 126 (S6), pp.96-103
ISSN
1742-7843
Publisher
Wiley
Start Page
96
End Page
103
Journal / Book Title
Basic and Clinical Pharmacology and Toxicology
Volume
126
Issue
S6
Copyright Statement
© 2019 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30901161
Subjects
In Vivo
AlbudAb
Apelin
Cardiovascular
G protein coupled receptor
Total word count = 6189
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2019-04-10