Cyclic thrombospondin-1 mimetics: grafting of a thrombospondin sequence into circular disulfide-rich frameworks to inhibit endothelial cell migration

Chan, Lai Yue, Craik, David J., and Daly, Norelle L. (2015) Cyclic thrombospondin-1 mimetics: grafting of a thrombospondin sequence into circular disulfide-rich frameworks to inhibit endothelial cell migration. Bioscience Reports, 35. e00270. pp. 1-12.

PDF (Published Version) - Published Version
Available under License Creative Commons Attribution.

Download (914kB) | Preview
View at Publisher Website:


Tumour formation is dependent on nutrient and oxygen supply from adjacent blood vessels. Angiogenesis inhibitors can play a vital role in controlling blood vessel formation and consequently tumour progression by inhibiting endothelial cell proliferation, sprouting and migration. The primary aim of the present study was to design cyclic thrombospondin-1 (TSP-1) mimetics using disulfide-rich frameworks for anti-angiogenesis therapies and to determine whether these peptides have better potency than the linear parent peptide. A short anti-angiogenic heptapeptide fragment from TSP-1 (GVITRIR) was incorporated into two cyclic disulfide-rich frameworks, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II) and SFTI-1 (sunflower trypsin inhibitor-1). The cyclic peptides were chemically synthesized and folded in oxidation buffers, before being tested in a series of in vitro evaluations. Incorporation of the bioactive heptapeptide fragment into the cyclic frameworks resulted in peptides that inhibited microvascular endothelial cell migration, and had no toxicity against normal primary human endothelial cells or cancer cells. Importantly, all of the designed cyclic TSP-1 mimetics were far more stable than the linear heptapeptide in human serum. The present study has demonstrated a novel approach to stabilize the active region of TSP-1. The anti-angiogenic activity of the native TSP-1 active fragment was maintained in the new TSP-1 mimetics and the results provide a new chemical approach for the design of TSP-1 mimetics.

Item ID: 42517
Item Type: Article (Research - C1)
ISSN: 1573-4935
Keywords: angiogenesis inhibitors; endothelial cells; non-toxic; peptide; stable; thrombospondin-1
Additional Information:

© 2015 Authors. This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution Licence 3.0.

Funders: National Medical and Health Research Council (NHMRC), Australian Research Council (ARC)
Projects and Grants: NHMRC APP1028509, NHMRC APP1026501, ARC FF110100226
Date Deposited: 10 Feb 2016 07:32
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
Downloads: Total: 1028
Last 12 Months: 106
More Statistics

Actions (Repository Staff Only)

Item Control Page Item Control Page