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

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system (RAAS), is a promising candidate as a treatment for cancer that reflects its antiproliferative 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 DDP3 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

Reverse translation of phase I biomarker findings links the activity of angiotensin-(1–7) to repression of hypoxia inducible factor-1α in vascular sarcomas

<p>Abstract</p> <p>Background</p> <p>In a phase I study of angiotensin-(1–7) [Ang-(1–7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1–7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged <it>in vitro</it>.</p> <p>Methods</p> <p>Plasma biomarkers were measured prior to Ang-(1–7) administration as well as 1, 2, 3, 4, and 6 hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, <it>in vitro</it> growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1–7) treatment in these cells.</p> <p>Results</p> <p>Tests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P = .007). Treatment of EOMA cells with increasing doses of Ang-(1–7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1–7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (<it>P</it> = .04) and hypoxia inducible factor 1α (HIF-1α) expression (<it>P</it> < .001).</p> <p>Conclusions</p> <p>Ang-(1–7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.</p

K2-237 b and K2-238 b: discovery and characterization of two new transiting hot Jupiters from K2

© 2018 The Author(s) Published by Oxford University Press on behalf of the Royal Astronomical Society. We report the discovery of two hot Jupiters orbiting the stars K2-237 and K2-238. We used photometric data from Campaigns 11 and 12 of the Kepler K2 mission and radial velocity data obtained using the HARPS, FEROS, and CORALIE spectrographs. K2-237 b and K2-238 b have masses of 1.60-0.11+0.11 and 0.86+-0.120.13MJup, radii of 1.65-0.08+0.07 and 1.30-0.14+0.15 RJup, and are orbiting their host stars in 2.18-and 3.20-d orbits, respectively. The large radius of K2-237 b leads us to conclude that this candidate corresponds to a highly inflated hot Jupiter. K2-238 b has a radius consistent with theoretical models, considering the high incident flux falling on the planet. We consider K2-237 b to be an excellent system for follow-up studies, since not only is it very inflated, but it also orbits a relatively bright star (V = 11.6)