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Rational Design of Antiangiogenic Helical Oligopeptides Targeting the Vascular Endothelial Growth Factor Receptors.

ABSTRACT: Tumor angiogenesis, essential for cancer development, is regulated mainly by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which are overexpressed in cancer cells. Therefore, the VEGF/VEGFR interaction represents a promising pharmaceutical target to fight cancer progression. The VEGF surface interacting with VEGFRs comprises a short ?-helix. In this work, helical oligopeptides mimicking the VEGF-C helix were rationally designed based on structural analyses and computational studies. The helical conformation was stabilized by optimizing intramolecular interactions and by introducing helix-inducing C?,?-disubstituted amino acids. The conformational features of the synthetic peptides were characterized by circular dichroism and nuclear magnetic resonance, and their receptor binding properties and antiangiogenic activity were determined. The best hits exhibited antiangiogenic activity in vitro at nanomolar concentrations and were resistant to proteolytic degradation.

SUBMITTER: Zanella S

PROVIDER: S-EPMC6449863 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Rational Design of Antiangiogenic Helical Oligopeptides Targeting the Vascular Endothelial Growth Factor Receptors.

Zanella Simone S Bocchinfuso Gianfranco G De Zotti Marta M Arosio Daniela D Marino Franca F Raniolo Stefano S Pignataro Luca L Sacco Giovanni G Palleschi Antonio A Siano Alvaro S AS Piarulli Umberto U Belvisi Laura L Formaggio Fernando F Gennari Cesare C Stella Lorenzo L

Frontiers in chemistry 20190329

Tumor angiogenesis, essential for cancer development, is regulated mainly by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which are overexpressed in cancer cells. Therefore, the VEGF/VEGFR interaction represents a promising pharmaceutical target to fight cancer progression. The VEGF surface interacting with VEGFRs comprises a short α-helix. In this work, helical oligopeptides mimicking the VEGF-C helix were rationally designed based on structural analyses and computa ...[more]

PMID: 30984741

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Project description:BACKGROUND:Age-related macular degeneration (AMD) is a common cause of severe vision loss in people 55 years and older. OBJECTIVES:The objective of this review was to investigate the effects of anti-VEGF (vascular endothelial growth factor) modalities for treating neovascular AMD. SEARCH STRATEGY:We searched CENTRAL, MEDLINE, EMBASE and LILACS. We handsearched ARVO abstracts for 2006, 2007 for ongoing trials. SELECTION CRITERIA:We included randomized controlled trials (RCTs). DATA COLLECTION AND ANALYSIS:Two review authors independently extracted data. We contacted trial authors for additional data. We summarized outcomes as relative risks (RR), number needed to treat (NNT) and weighted mean differences. MAIN RESULTS:We included five RCTs of good methodological quality. All five trials were conducted by pharmaceutical companies. An intention-to-treat analysis using the last observation carried forward method was done in most trials. Two trials compared pegaptanib versus sham. One trial compared ranibizumab versus sham, another compared ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and the final trial compared ranibizumab plus verteporfin PDT versus verteporfin PDT alone. Fewer patients treated with pegaptanib lost 15 or more letters of visual acuity at one year follow-up compared to sham (pooled relative risk (RR) 0.71; 95% confidence interval (CI) 0.61 to 0.84). The NNT was 6.67 (95% CI 4.35 to 14.28) for 0.3 mg pegaptanib, 6.25 (95% CI 4.17 to 12.5) for 1 mg pegaptanib and 14.28 (95% CI 6.67 to 100) for 3 mg pegaptanib. In a trial of ranibizumab versus sham, RR for loss of 15 or more letters visual acuity at one year was 0.14 (95% CI 0.1 to 0.22) in favour of ranibizumab. The NNT was 3.13 (95% CI 2.56 to 3.84) for 0.3 mg ranibizumab and 3.13 (95% CI 2.56 to 3.84) for 0.5 mg ranibizumab. In a trial of ranibizumab versus verteporfin PDT, RR for loss of 15 or more letters at one year was 0.13 (95% CI 0.07 to 0.23) favouring ranibizumab. The NNT was 3.33 (95% CI 2.56 to 4.76) for 0.3 mg ranibizumab and 3.12 (95% CI 2.43 to 4.17) for 0.5 mg ranibizumab. In another trial of combined ranibizumab plus verteporfin PDT versus verteporfin PDT, RR for loss of 15 or more letters at one year favoured combined therapy (RR 0.3 (95% CI 0.15 to 0.60). The NNT was 4.35 (95% CI 2.78 to 11.11). Pooled RR for gain of 15 or more letters visual acuity at one year was 5.81 (95% CI 3.29 to 10.26) for ranibizumab versus sham, 6.79 (95% CI 3.41 to 13.54) for ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and 4.44 (95% CI 1.40 to 14.08) for ranibizumab plus verteporfin PDT versus verteporfin PDT. Frequency of endophthalmitis in included studies was between 0.7% to 4.7% with ranibizumab and 1.3% with pegaptanib. Improvement in vision-specific quality of life was reported for both treatments. AUTHORS' CONCLUSIONS:Pegaptanib and ranibizumab reduce the risk of visual acuity loss in patients with neovascular AMD. Ranibizumab causes gains in visual acuity in many eyes. Quality of life and cost will be important for treatment decisions. Other agents blocking VEGF are being tested in ongoing trials.

Dataset Information

Rational Design of Antiangiogenic Helical Oligopeptides Targeting the Vascular Endothelial Growth Factor Receptors.

Publications

Rational Design of Antiangiogenic Helical Oligopeptides Targeting the Vascular Endothelial Growth Factor Receptors.

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