Biomolecules able to modulate the VEGF-dependent angiogenesis
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Biomolecules able to modulate the VEGF-dependent angiogenesis
Research areas: Macromolecules for biomedical and biotechnological applications, Structure and function of proteins involved in physio-pathologic processes, Small molecules and peptides/modified peptides for diagnostic, therapeutic and biotechnological applications, Other Diseases, Cancer Diseases, 

Keywords: VEGF, Angiogenesis, Molecular Design, Bioactive peptides, Recombinant VEGF receptor domains, Protein folding

Contact person: Luca Domenico D'Andrea, 

Actors: Sonia Di Gaetano, digaetanunina.it, Donatella Diana, donatella.diana@cnr.it, Rossella Di Stasi, rossella.distasicnr.it, Lucia De Rosa, lucia.derosaunina.it, Luca Domenico D'Andrea,

Description:
Vascular Endothelial Growth Factor (VEGF) is a potent angiogenic factor, a mitogen specific for vascular endothelial cells and plays a major role in physiologic and pathological angiogenesis. It induces ECs proliferation, migration, survival and increases vascular permeability. VEGF is involved in several diseases dependent on excessive and insufficient angiogenesis making the molecular system, VEGF-receptors, a target for therapeutic and diagnostic applications. The biological function of VEGF is mediated by binding to two tyrosine kinase receptors, VEGFR1 (Flt1) and VEGFR2 (KDR). VEGF induces receptor dimerization which triggers kinase domain autophosphorylation and activation of intracellular pathways. Molecules able to bind to VEGF or VEGFRs could modulate VEGF biological activity and find application in both therapy and receptor imaging. Our research group has long been interested in the study of the VEGF/receptors axis through the development of peptide molecules and the expression and characterization of recombinant proteins able to  modulate VEGF-dependent angiogenesis. In particular, starting from the X-ray structure of the complex between VEGF and the extracellular domain 2 of VEGFR1 (VEGFR1D2), we designed a series of peptide molecules reproducing two VEGF interacting regions, the N-terminal helix 17-25 and the beta-hairpin 79-91. A series of bioactive peptides working as VEGF agonists or antagonists were developed. Such molecules show biomedical applications for the therapy and diagnosis of diseases associated with insufficient (e.g. ischemic and cardiovascular diseases) or excessive angiogenesis (e.g. cancer, age-related macular degeneration). The expression and purification of some of the extracellular domains of the VEGFR1 (VEGFR1-D2) and VEGFR2 (VEGFR2-D4 and -D7) receptors has allowed us to characterize by NMR spectroscopy, even in the presence of whole endothelial cells, the binding interfaces between the designed peptides and the protein partners. Furthermore, the recombinant expression of VEGF isoforms 165 and 121 confirmed, through the use of protein-protein interaction techniques, such as surface plasmon resonance (SPR), microscale thermophoresis (MST) and ELISA assays, the affinity constants between VEGF and its receptor domains. In the case of VEGFR2-D4, we developed a monoclonal antibody recognizing VEGFR2 domain 4 to study its ability to inhibit VEGFR2 dimerization  


Figures:

Backbone superposition of the QK representative structure (yellow) and VEGF helix (red) bound to Flt-1D2 (1FLT). Side-chain of the interacting residues and the Flt-1D2 electrostatic surface are shown.


Selected papers:

Biochemical and conformational characterization of recombinant VEGFR2 domain 7. Di Stasi R, Diana D, De Rosa L, Fattorusso R, D’Andrea L D. Molecular Biotechnology. 2019, 61, 860–872. DOI: 10.1007/s12033-019-00211-4; Human recombinant VEGFR2D4 biochemical characterization to investigate novel anti-VEGFR2D4 antibodies for allosteric targeting of VEGFR2. Di Stasi R, Diana D, De Rosa L, Fattorusso R, D’Andrea L D. Molecular Biotechnology. 2019, 61, 513–520. DOI: 10.1007/s12033-019-00181-7; Structural studies of the binding of an antagonistic cyclic peptide to the VEGFR1 domain 2. Wang L, Coric P, Broussy S, Di Stasi R, Zhou L, D'Andrea L D, Ji L, Vidal M, Bouaziz S, Liu W Q. European Journal of Medicinal Chemistry. 2019, 169, 65-75. DOI: 10.1016/j.ejmech.2019.02.069; Pro-angiogenic peptides in biomedicine. De Rosa L, Di Stasi R, D’Andrea L D. Archives of Biochemistry and Biophysics. 2018, 660, 72–86. DOI: 10.1016/j.abb.2018.10.010; VEGFR recognition interface of a proangiogenic VEGF-mimetic peptide as determined in vitro and in presence of endothelial cells by NMR spectroscopy. Di Stasi R, Diana D, Capasso D, Di Gaetano S, De Rosa L, Celentano V, Isernia C, Fattorusso R, D'Andrea L D. Chemistry A European Journal 2018, 24, 11461-11466. DOI: 10.1002/chem.201802117; Unveiling a VEGF-mimetic peptide sequence in the IQGAP1 protein. Capasso D, Di Gaetano S, Celentano V, Diana D, Festa L, Di Stasi R, De Rosa L, Fattorusso R, D'Andrea L D. Molecular Biosystems. 2017, 13(8), 1619-1629. DOI: 10.1039/c7mb00190h; Peptides Interacting with Growth Factor Receptors Regulating Angiogenesis. Di Stasi R, De Rosa L, Romanelli A, D'Andrea L D. Frontiers in Medicinal Chemistry. 2016, 9, 103-160. DOI: 10.2174/9781681082493116090006; Miniaturizing VEGF: Peptides mimicking the discontinuous VEGF receptor-binding site modulate the angiogenic response. De Rosa L, Finetti F, Diana D, Di Stasi R, Auriemma S, Romanelli A, Fattorusso R, Ziche M, Morbidelli L, D'Andrea L D.  Scientific reports-Nature. 2016, 6, 31295. DOI: 10.1038/srep31295; Functional binding surface of a β-hairpin VEGF receptor targeting peptide determined by NMR spectroscopy in living cells. Diana D, Russomanno A, De Rosa L, Di Stasi R, Capasso D, Di Gaetano S, Romanelli A, Russo L, D'Andrea L D, Fattorusso R. Chemistry A European Journal. 2015, 21(1), 91-5. DOI: 10.1002/chem.201403335; Long range Trp-Trp interaction initiates the folding pathway of a pro-angiogenic β-hairpin peptide. Diana D, De Rosa L, Palmieri M, Russomanno A, Russo L, La Rosa C, Milardi D, Colombo G, D'Andrea L D, Fattorusso R. Scientific Reports-Nature. 2015, 5, 16651. DOI: 10.1038/srep16651; Design, structural and biological characterization of a VEGF inhibitor β-hairpin-constrained peptide. De Rosa L, Diana D, Basile A, Russomanno A, Isernia C, Turco M C, Fattorusso R, D'Andrea L D. European Journal of Medicinal Chemistry. 2014, 73, 210-6. DOI: 10.1016/j.ejmech.2013.12.016; Structural investigation of the VEGF receptor interaction with a helical antagonisti peptide. Diana D, Di Stasi R, De Rosa L, Isernia C, D'Andrea L D, Fattorusso R. Journal of Peptide Science. 2013, 19 (4), 214-219. DOI: 10.1002/psc.2480; Functional and pharmacological characterization of a VEGF mimetic peptide on reparative angiogenesis. Finetti F, Basile A, Capasso D, Di Gaetano S, Di Stasi R, Pascale M, Turco M C, Ziche M, Morbidelli L, D'Andrea L D. Biochemical Pharmacology. 2012, 84(3), 303-11. DOI: 10.1016/j.bcp.2012.04.011; C-terminal truncation of Vascular Endothelial Growth Factor mimetic helical peptide preserves structural and receptor binding properties. Ziaco B, Diana D, Capasso D, Palumbo R, Celentano V, Di Stasi R, Fattorusso R, D'Andrea L D. Biochemical and Biophysical Research Communications. 2012, 424(2), 290-4. DOI:10.1016/j.bbrc.2012.06.109; β-hairpin peptide that targets vascular endothelial growth factor (VEGF) receptors: design, NMR characterization, and biological activity. Diana D, Basile A, De Rosa L, Di Stasi R, Auriemma S, Arra C, Pedone C, Turco M C, Fattorusso R, D'Andrea L D. Journal of Biological Chemistry. 2011, 286(48), 41680–41691. DOI: 10.1074/jbc.M111.257402; Characterization of a designed Vascular Endothelial Growth Factor receptor antagonist helical peptide with antiangiogenic activity in vivo. Basile A, Del Gatto A, Diana D, Di Stasi R, Falco A, Festa M, Rosati A, Barbieri A, Franco R, Arra C, Pedone C, Fattorusso R, Turco M C, D'Andrea L D. Journal of Medicinal Chemistry. 2011, 54(5), 1391-400. DOI: 10.1021/jm101435r; Biochemical and structural analysis of the binding determinants of a Vascular Endothelial Growth Factor receptor peptidic antagonist. Gautier B, Victor G, Diana D, Di Stasi R, Teillet F, Lenoir C, Huguenot F, Garbay C, Fattorusso R, D'Andrea L D, Vidal M, Inguimbert N. Journal of Medicinal Chemistry. 2010, 53, 11, 4428–4440. DOI: 10.1021/jm1002167; VEGFR1D2 in drug discovery: expression and molecular characterization. Di Stasi R, Diana D, Capasso D, Palumbo R, Romanelli A, Pedone C, Fattorusso R, D'Andrea L D. Biopolymers. 2010, 94(6), 800-9. DOI: 10.1002/bip.21448; Bioinorganic aspects of angiogenesis. D'Andrea L D, Romanelli A, Di Stasi R, Pedone C. Dalton Transactions. 2010, 39(33), 7625-36. DOI: 10.1039/c002439b; NMR and computational analysis of the unfolding pathway of a VEGF mimicking helical peptide. Diana D, Ziaco B, Scarabelli G, Pedone C, Colombo G, D’Andrea L D, Fattorusso R. Chemistry-A European Journal. 2010, 16, 5400-54078; Peptides targeting angiogenesis related growth factor receptors. D’Andrea L D, Del Gatto A, De Rosa L, Romanelli A, Pedone C. Current Pharmaceutical Design. 2009, 15, 2414-24296. DOI: 10.2174/138161209788682235; In vivo properties of the proangiogenic peptide QK. Santulli G, Ciccarelli M, Palumbo G, Campanile A, Galasso G, Ziaco B, Altobelli G G, Cimini V, Piscione F, D’Andrea L D, Pedone C, Trimarco B, Iaccarino G. Journal of Translational Medicine. 2009, 7, 417. DOI: 10.1186/1479-5876-7-41; Structural determinants of the unusual helix stability of a de novo engineered VEGF mimicking peptide. Diana D, Ziaco B, Colombo G, Scarabelli G, Romanelli A, Pedone C, Fattorusso R, D’Andrea L.D. Chemistry-A European. Journal. 2008, 14, 4164-41664. DOI: 10.1002/chem.200800180; A Vascular Endothelial Growth Factor Mimetic Accelerates Gastric Ulcer Healing in an iNOS-Dependent Manner. Dudar G K, D'Andrea L D, Di Stasi R, Pedone C, Wallace J L. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2008, 295(2), G374-81. DOI: 10.1152/ajpgi.90325; Peptide-based Molecules in Angiogenesis. D’Andrea L D, Del Gatto A, Pedone C, Benedetti E. Chemical Biology & Drug Design. 2006, 67, 1151263. DOI: 10.1111/j.1747-0285.2006.00356.x; Targeting angiogenesis: structural characterization and biological properties of a de novo engineered VEGF mimicking peptide. D’Andrea L D, Iaccarino G, Fattorusso R, Sorriento D, Carannante C, Capasso D, Trimarco B, Pedone. C. Proc. Natl. Acad. Sci. USA. 2005, 102, 14215-142202. DOI: 10.1073/pnas.0505047102; D’Andrea et al., PCT/EP 2006/00631414; DAndrea et al., PCT/EP201/060722.

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Last modified by Rossella Di Stasi on Tuesday 01 December 2020, 13:21:46
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