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A novel bioengineered fragment peptide of Vasostatin-1 exerts smooth muscle pharmacological activities and anti-angiogenic effects via blocking VEGFR signalling pathway
Wei, Ran1,2; Wu, Qiushuang2,3; Ai, Nana4; Wang, Lei5; Zhou, Mei5; Shaw, Chris5; Chen, Tianbao5; Ye, Richard Dequan6; Ge, Wei4; Siu, Shirley W.I.7; Kwok, Hang Fai2,3
2021-01
Source PublicationComputational and Structural Biotechnology Journal
ISSN2001-0370
Volume19Pages:2664-2675
Abstract

Chromogranin A (CgA) is a hydrophilic glycoprotein released by post-ganglionic sympathetic neurons. CgA consists of a single peptide chain containing numerous paired basic residues, which are typical cleavage sites in prohormones to generate bioactive peptides. It is recognized as a diagnostic and prognostic serum marker for neuroendocrine tumours. Vasostatin-1 is one of the most conserved regions of CgA and has diverse inhibitory biological activities. In this study, a novel peptide fragment that contains three typical functional structures of Vasostatin-1 was synthesized. This unique bioengineered Vasostatin-1 Derived Peptide (named V1DP) includes a highly conserved domain between vertebrate species in its N-terminal region, comprising a disulphide bridge formed by two cysteine residues at amino acid positions 17 and 38, respectively. Besides, V1DP contains two significant tripeptide recognition sequences: the amino acid triplets, RGD and KGD. Our data demonstrated that V1DP could induce a dose-dependent relaxation of rat arterial smooth muscle and also increase the contraction activity of rat uterus smooth muscle. More importantly, we found that V1DP inhibits cancer cell proliferation, modulate the HUVEC cell migration, and exhibit anti-angiogenesis effect both in vitro and in vivo. We further investigated the actual mechanism of V1DP, and our results confirmed that V1DP involves inhibiting the vascular endothelial growth factor receptor (VEGFR) signalling. We docked V1DP to the apo structures of VEGFR2 and examined the stability of the peptide in the protein pockets. Our simulation and free energy calculations results indicated that V1DP can bind to the catalytic domain and regulatory domain pockets, depending on whether the conformational state of the protein is JM-in or JM-out. Taken together, our data suggested that V1DP plays a role as the regulator of endothelial cell function and smooth muscle pharmacological homeostasis. V1DP is a water-soluble and biologically stable peptide and could further develop as an anti-angiogenic drug for cancer treatment.

KeywordAnti-angiogenesis Chromogranin a Vasostatin-1 Vegfr2
DOI10.1016/j.csbj.2021.05.003
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaBiochemistry & Molecular Biology ; Biotechnology & Applied Microbiology
WOS SubjectBiochemistry & Molecular Biology ; Biotechnology & Applied Microbiology
WOS IDWOS:000684856500002
Scopus ID2-s2.0-85105598297
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Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorKwok, Hang Fai
Affiliation1.CCZU-JITRI Joint Bio-X Lab, School of Pharmacy & School of Medicine, Changzhou University, Changzhou, China; Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, China
2.Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, China
3.Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, China
4.Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, Avenida de Universidade, University of Macau, Macau SAR, China
5.Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, United Kingdom
6.School of Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, China
7.Department of Computer and Information Science, Faculty of Science and Technology, University of Macau, Avenida de Universidade, Taipa, China
First Author AffilicationCancer Centre;  Faculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences;  Cancer Centre
Recommended Citation
GB/T 7714
Wei, Ran,Wu, Qiushuang,Ai, Nana,et al. A novel bioengineered fragment peptide of Vasostatin-1 exerts smooth muscle pharmacological activities and anti-angiogenic effects via blocking VEGFR signalling pathway[J]. Computational and Structural Biotechnology Journal,2021,19:2664-2675.
APA Wei, Ran,Wu, Qiushuang,Ai, Nana,Wang, Lei,Zhou, Mei,Shaw, Chris,Chen, Tianbao,Ye, Richard Dequan,Ge, Wei,Siu, Shirley W.I.,&Kwok, Hang Fai.(2021).A novel bioengineered fragment peptide of Vasostatin-1 exerts smooth muscle pharmacological activities and anti-angiogenic effects via blocking VEGFR signalling pathway.Computational and Structural Biotechnology Journal,19,2664-2675.
MLA Wei, Ran,et al."A novel bioengineered fragment peptide of Vasostatin-1 exerts smooth muscle pharmacological activities and anti-angiogenic effects via blocking VEGFR signalling pathway".Computational and Structural Biotechnology Journal 19(2021):2664-2675.
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