Stabilization of Angiotensin-(1-7) by Key Substitution with a Cyclic Non-natural Amino Acid

Overview

Journal Amino Acids

Specialty Biochemistry

Date 2017 Jul 27

PMID 28744580

Citations 6

Authors

Anita Wester

Marc Devocelle

E Ann Tallant

Mark C Chappell

Patricia E Gallagher

Francesca Paradisi

Affiliations

Soon will be listed here.

Abstract

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer.

Citing Articles

Non-Canonical Amino Acids in Analyses of Protease Structure and Function.

Goettig P, Koch N, Budisa N Int J Mol Sci. 2023; 24(18).

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Therapeutic Approaches to the Alternative Angiotensin-(1-7) Axis of the Renin-Angiotensin System.

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America Chi L, Asgharpour S, Correa-Basurto J, Bandala C, Martinez-Archundia M J Comput Aided Mol Des. 2022; 36(9):653-675.

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Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics.

Ding Y, Ting J, Liu J, Al-Azzam S, Pandya P, Afshar S Amino Acids. 2020; 52(9):1207-1226.

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Fetal Growth Restriction and Hypertension in the Offspring: Mechanistic Links and Therapeutic Directions.

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