Amino Acids

, Volume 49, Issue 10, pp 1733–1742 | Cite as

Stabilization of Angiotensin-(1–7) by key substitution with a cyclic non-natural amino acid

  • Anita Wester
  • Marc Devocelle
  • E. Ann Tallant
  • Mark C. Chappell
  • Patricia E. Gallagher
  • Francesca Paradisi
Original Article

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.

Keywords

Peptidomimetic Non-natural amino acid Angiotensin-(1–7) Angiotensin-converting enzyme Dipeptidyl peptidase 3 ACCA 

Abbreviations

ACCA

cis-3-(Aminomethyl)cyclobutanecarboxylic acid

ACE

Angiotensin-converting enzyme

HATU

N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide

HEPES

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

HPLC

High-performance liquid chromatography

HRMS

High-resolution mass spectrometry

2CT resin

2-Chlorotrityl resin

NMP

N-methylpyrrolidone

DIPEA

N,N-Diisopropylethylamine

DPP 3

Dipeptidyl peptidase 3

Fmoc

9-Fluorenylmethoxycarbonyl

Fmoc-OSu

N-(9-Fluorenylmethoxycarbonyloxy)succinimide

Pbf

2,2,4,6,7-Pentamethyldihydrobenzyofuran-5-sulfonyl

t-Bu

t-Butyl

Trt

Trityl

TFA

Trifluoroacetic acid

SPPS

Solid-phase peptide synthesis

Supplementary material

726_2017_2471_MOESM1_ESM.docx (1.5 mb)
Supplementary material 1 (DOCX 1577 kb)

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Copyright information

© Springer-Verlag GmbH Austria 2017

Authors and Affiliations

  1. 1.School of ChemistryUniversity College DublinDublinIreland
  2. 2.Department of Pharmaceutical and Medicinal Chemistry, Centre for Synthesis and Chemical BiologyRoyal College of Surgeons in IrelandDublinIreland
  3. 3.Surgery/Hypertension and Vascular ResearchWake Forest School of MedicineWinston-SalemUSA
  4. 4.School of ChemistryUniversity of NottinghamNottinghamUK

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