Synthetic heparan sulfate ligands for vascular endothelial growth factor to modulate angiogenesis

Jain, Prashant Ankur; Shanthamurthy, Chethan D.; Ben-Arye, Shani Leviatan; Yehuda, Sharon; Nandikol, Sharvani S; Thulasiram, Hirekodathakallu V.; Padler‐Karavani, Vered; Kikkeri, Raghavendra

doi:10.1039/d1cc00964h

Cited by 12 publications

(8 citation statements)

References 55 publications

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“…Additionally, they showed that this HS mimetic, potentially by binding to CCL2, inhibits breast cancer CCL2-mediated cell proliferation and CCR2/CCL2mediated cell migration, and it reduces cell invasiveness (130). More recently, Jain P. cellular events, as these were shown to not only bind with high affinity to the mentioned growth factor but also to inhibit endothelial cells' VEGF 165 -induced proliferation, migration and tube formation, which are known to be relevant tumour related features (131).…”

Section: Hs Mimeticsmentioning

confidence: 99%

“…Additionally, they showed that this HS mimetic, potentially by binding to CCL2, inhibits breast cancer CCL2-mediated cell proliferation and CCR2/CCL2- mediated cell migration, and it reduces cell invasiveness ( 130 ). More recently, Jain P. et al have resorted to a library of HS tetrasaccharide ligands with varying sulfation patterns and high-throughput array binding assays to further address HS binding specificities, and validated two HS analogues, HT-2,6S-NAc and HT-6S-NAc, as potential ligands to target VEGF 165 -mediated cellular events, as these were shown to not only bind with high affinity to the mentioned growth factor but also to inhibit endothelial cells’ VEGF 165 -induced proliferation, migration and tube formation, which are known to be relevant tumour related features ( 131 ).…”

Section: Targeting Of Hs and Hs Biosynthetic Enzymesmentioning

confidence: 99%

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Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

et al. 2021

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Heparan Sulfate Proteoglycans (HSPGs) are important cell surface and Extracellular Matrix (ECM) maestros involved in the orchestration of multiple cellular events in physiology and pathology. These glycoconjugates bind to various bioactive proteins via their Heparan Sulfate (HS) chains, but also through the protein backbone, and function as scaffolds for protein-protein interactions, modulating extracellular ligand gradients, cell signalling networks and cell-cell/cell-ECM interactions. The structural features of HS chains, including length and sulfation patterns, are crucial for the biological roles displayed by HSPGs, as these features determine HS chains binding affinities and selectivity. The large HS structural diversity results from a tightly controlled biosynthetic pathway that is differently regulated in different organs, stages of development and pathologies, including cancer. This review addresses the regulatory mechanisms underlying HS biosynthesis, with a particular focus on the catalytic activity of the enzymes responsible for HS glycan sequences and sulfation motifs, namely D-Glucuronyl C5-Epimerase, N- and O-Sulfotransferases. Moreover, we provide insights on the impact of different HS structural epitopes over HSPG-protein interactions and cell signalling, as well as on the effects of deregulated expression of HS modifying enzymes in the development and progression of cancer. Finally, we discuss the clinical potential of HS biosynthetic enzymes as novel targets for therapy, and highlight the importance of developing new HS-based tools for better patients’ stratification and cancer treatment.

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Section: Hs Mimeticsmentioning

confidence: 99%

Section: Targeting Of Hs and Hs Biosynthetic Enzymesmentioning

confidence: 99%

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

et al. 2021

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“…Similar results were observed for the heparin binding epidermal growth factor (HB-EGF) and amphiregulin (Figure ), which are both classified as ligands that bind EGF receptors (EGFRs). , Of note, FGF2 showed low binding to all four negative control Sia-glycans. In contrast, bone morphogenic protein-2 (BMP2) and VEGF 165 , a key synergistic mediator in osteogenesis and angiogenesis, , exhibited unexpected strong binding to I-11 and I-21 (ranked 83 and 91% with BMP2 and 88 and 99% with VEGF 165 ), whereas 1–31 and I-41 displayed moderate to poor binding (ranked 73 and 47% with BMP2 and 59 and 5% with VEGF 165 ). Of note, the binding to intermediate sulfated analogs was higher than the binding to natural heparin, and binding to Sia-glycan negative control was low.…”

Section: Results and Discussionmentioning

confidence: 99%

Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate

et al. 2021

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Recently, the activity of heparan sulfate (HS) has led to the discovery of many drug candidates that have the potential to impact both medical science and human health. However, structural diversity and synthetic challenges impede the progress of HS research. Here, we report a library of novel l-iduronic acid (IdoA)-based HS mimics that are highly tunable in conformation plasticity and sulfation patterns to produce many of the functions of native HS oligosaccharides. The NMR analysis of HS mimics confirmed that 4-O-sulfation enhances the population of the 1C4 geometry. Interestingly, the 1C4 conformer becomes exclusive upon additional 2-O-sulfation. HS mimic microarray binding studies with different growth factors showed that selectivity and avidity are greatly modulated by the oligosaccharide length, sulfation code, and IdoA conformation. Particularly, we have identified 4-O-sulfated IdoA disaccharide (I-21) as a potential ligand for vascular endothelial growth factor (VEGF165), which in a multivalent display modulated endothelial cell proliferation, migration, and angiogenesis. Overall, these results encourage the consideration of HS mimics for therapeutic applications.

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“…In recent years, a series of other peptides were also reported. For example, peptides deriving from the binding domain of various VEGF receptors such as Flt-1, KDR, were demonstrated to bind with VEGF 42,43 ; and peptides deriving from heparin were also revealed to have specific affinity with VEGF 44,45 ; other peptides were also screened by phage displayed library to serve as the "ligand-targeting" peptide of VEGF. 46 These peptides combining with VEGF showed to increase the angiogenesis in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Functional recovery of myocardial infarction by specific EBP‐PR1P peptides bridging injectable cardiac extracellular matrix and vascular endothelial growth factor

Cao

Zhang

Zhou

et al. 2022

J Biomedical Materials Res

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Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor and plays an important role in therapy of myocardial infarction (MI). Currently, how to retain regional concentration and decrease rapid diffusion is critical for its clinical application of VEGF. In recent years, the application of targeting peptides has been developed rapidly and provides new strategies for the sustained release of VEGF. In present study, a bi‐functional EBP‐PR1P peptide was designed and bridged VEGF to injectable cardiac extracellular matrix (c‐ECM). Through EBP‐PR1P peptides, VEGF could specifically bind with c‐ECM to realize the sustained release, without impacting the bioactivity of VEGF. Then VEGF/EBP‐PR1P/c‐ECM scaffolds were constructed and administrated into rats with MI. The results showed VEGF/EBP‐PR1P/c‐ECM could promote angiogenesis, protect cardiomyocytes survival against apoptosis, and improve the recovery of cardiac function. In addition, the mechanism of EBP‐PR1P/VEGF was also investigated which canonical downstream of VEGF‐Akt signaling pathway was activated. These results showed specific VEGF/EBP‐PR1P/c‐ECM scaffolds served as promising delivery system for VEGF that facilitated the functional recovery of MI.

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Synthetic heparan sulfate ligands for vascular endothelial growth factor to modulate angiogenesis

Abstract: We report the discovery of a potential heparan sulfate (HS) ligand to target several growth factors using 13 unique HS tetrasaccharide ligands. By employing an HS microarray and SPR, we...

Cited by 12 publications

References 55 publications

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate

Functional recovery of myocardial infarction by specific EBP‐PR1P peptides bridging injectable cardiac extracellular matrix and vascular endothelial growth factor

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