Imperial College London
Alternate

ProfessorRobertGlen

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Computational Medicine
 
 
 
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Contact

 

+44 (0)20 7594 7912r.glen Website

 
 
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Location

 

362Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Read:2020:10.1111/bcpt.13227,
author = {Read, C and Yang, P and Kuc, RE and Nyimanu, D and Williams, TL and Glen, RC and Holt, LJ and Arulanantham, H and Smart, A and Davenport, AP and Maguire, JJ},
doi = {10.1111/bcpt.13227},
journal = {Basic and Clinical Pharmacology and Toxicology},
pages = {96--103},
title = {Apelin peptides linked to anti-serum albumin domain antibodies retain affinity in vitro and are efficacious receptor agonists in vivo},
url = {http://dx.doi.org/10.1111/bcpt.13227},
volume = {126},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Read,C
AU  - Yang,P
AU  - Kuc,RE
AU  - Nyimanu,D
AU  - Williams,TL
AU  - Glen,RC
AU  - Holt,LJ
AU  - Arulanantham,H
AU  - Smart,A
AU  - Davenport,AP
AU  - Maguire,JJ
DO  - 10.1111/bcpt.13227
EP  - 103
PY  - 2020///
SN  - 1742-7843
SP  - 96
TI  - Apelin peptides linked to anti-serum albumin domain antibodies retain affinity in vitro and are efficacious receptor agonists in vivo
T2  - Basic and Clinical Pharmacology and Toxicology
UR  - http://dx.doi.org/10.1111/bcpt.13227
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30901161
UR  - https://onlinelibrary.wiley.com/doi/full/10.1111/bcpt.13227
UR  - http://hdl.handle.net/10044/1/69502
VL  - 126
ER  -
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