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Improved pharmacokinetics and bone tissue accumulation of Angiotensin-(1–7) peptide through bisphosphonate conjugation

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Abstract

The renin–angiotensin system (RAS) has a central role in renal and cardiovascular homeostasis. Angiotensin-(1–7) (Ang1–7), one of the RAS active peptides, exerts beneficial effects through different mechanisms. These biological actions suggest that Ang1–7 is an effective therapeutic agent for treating various diseases associated with activated RAS. However, its short half-life and poor pharmacokinetics restrict its therapeutic utility. Our laboratory has successfully synthesized and characterized an Ang1–7 conjugate (Ang Conj.) with a prolonged half-life and improved pharmacokinetics profile. The Ang Conj. has been prepared by PEGylation of Ang1–7 and conjugation with a bisphosphonate using solid-phase peptide synthesis and characterized by HPLC and mass spectrometer. The compound’s stability has been tested in different storage conditions. The bone binding capacity was evaluated using a hydroxyapatite assay. Pharmacokinetic and tissue distribution studies were performed using iodinated peptides in rats. Ang Conj. was synthesized with > 90% purity. Bone mineral affinity testing showed Ang Conj. exhibited significantly higher bone mineral affinity than Ang1–7. The Ang Conj. remained stable for more than a month using all tested storage conditions. The Ang Conj. demonstrated higher affinity to bone, a longer half-life, and better bioavailability when compared with the native peptide. These results support that conjugation of Ang1–7 with bisphosphonate enables it to utilize bone as a reservoir for the sustained delivery of Ang1–7 to maintain therapeutic plasma levels. High chemical stability and about five to tenfold prolongation of Ang Conj. plasma half-life after administrations into rats proves the effectiveness of our approach.

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Acknowledgements

The authors want to thank Dr. Jared Barrott for his help in animal blood sampling and Mary van Muelken for her efforts in proofreading this manuscript.

Funding

The authors did not receive support from any organization for the submitted work.

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Authors and Affiliations

  1. College of Pharmacy, Idaho State University, Pocatello, ID, USA

    Ali Aghazadeh-Habashi & Sana Khajehpour

  2. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Leonard Hall 212, Pocatello, ID, 83209-8288, USA

    Ali Aghazadeh-Habashi

Authors
  1. Ali Aghazadeh-Habashi
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  2. Sana Khajehpour
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Contributions

AAH did the study design, synthesis of Ang1–7 conjugate, animal dosing and sampling, tissue distribution and PK studies, drafting the manuscript. The stability study, HPLC analysis, HA binding study, data interpretation, data analysis, revising manuscript content, and approving the final version of the manuscript were made by AAH and SK.

Corresponding author

Correspondence to Ali Aghazadeh-Habashi.

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Conflict of interest (include appropriate disclosures)

The novel approach of conjugate synthesis was filed for a US patent application on July, 24, 2020, by the corresponding author. No author has an actual or perceived conflict of interest with the contents of this article.

Ethics approval (include appropriate approvals or waivers)

The animal protocol No. 760 was approved by the Idaho State University Institutional Animal Care and Use Committee.

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Handling Editor: M. S. Palma.

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Aghazadeh-Habashi, A., Khajehpour, S. Improved pharmacokinetics and bone tissue accumulation of Angiotensin-(1–7) peptide through bisphosphonate conjugation. Amino Acids 53, 653–664 (2021). https://doi.org/10.1007/s00726-021-02972-2

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  • DOI: https://doi.org/10.1007/s00726-021-02972-2

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