Abstract
Pharmacological strategies aimed at preventing cancer growth are in most cases paralleled by diagnostic investigations for monitoring and prognosticating therapeutic efficacy. A relevant approach in cancer is the suppression of pathological angiogenesis, which is principally driven by vascular endothelial growth factor (VEGF) or closely related factors and by activation of specific receptors, prevailingly VEGFR1 and VEGFR2, set on the surface of endothelial cells. Monitoring the presence of these receptors in vivo is henceforth a way to predict therapy outcome. We have designed small peptides able to bind and possibly antagonize VEGF ligands by targeting VEGF receptors. Peptide systems have been designed to be small, cyclic and to host triplets of residues known to be essential for VEGF receptors recognition and we named them ‘mini-factors’. They have been structurally characterized by CD, NMR and molecular dynamics (MD) simulations. Mini-factors do bind with different specificity and affinity VEGF receptors but none blocks receptor activity. Following derivatization with suitable tracers they have been employed as molecular probes for sensing receptors on cell surface without affecting their activity as is usually observed with other binders having neutralizing activity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Albini A et al (1996) The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nat Med 2:1371–1375. https://doi.org/10.1038/nm1296-1371
Binetruy-Tournaire R et al (2000) Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis. EMBO J 19:1525–1533. https://doi.org/10.1093/emboj/19.7.1525
Byrne AM, Bouchier-Hayes DJ, Harmey JH (2005) Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9:777–794
Calvanese L et al (2015) Conformational features and binding affinities to cripto, ALK7 and ALK4 of nodal synthetic fragments. J Pept Sci 21:283–293. https://doi.org/10.1002/psc.2733
Caporale A, Sturlese M, Schievano E, Mammi S, Peggion E (2010) Synthesis and structural studies of new analogues of PTH(1–11) containing calpha-tetra-substituted amino acids in position 8. Amino Acids 39:1369–1379. https://doi.org/10.1007/s00726-010-0591-6
Caporale A, Gesiot L, Sturlese M, Wittelsberger A, Mammi S, Peggion E (2012) Design, conformational studies and analysis of structure–function relationships of PTH (1–11) analogues: the essential role of val in position 2. Amino Acids 43:207–218. https://doi.org/10.1007/s00726-011-1065-1
Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257. https://doi.org/10.1038/35025220
Chorev M (2005) The partial retro-inverso modification: a road traveled together. Biopolymers 80:67–84. https://doi.org/10.1002/bip.20219
D’Andrea LD, Romanelli A, Di Stasi R, Pedone C (2010) Bioinorganic aspects of angiogenesis. Dalton Trans 39:7625–7636. https://doi.org/10.1039/c002439b
De Rosa L et al (2016) Miniaturizing VEGF: peptides mimicking the discontinuous VEGF receptor-binding site modulate the angiogenic response. Sci Rep 6:31295. https://doi.org/10.1038/srep31295
Detmar M et al (1994) Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 180:1141–1146
Etayash H, Jiang K, Azmi S, Thundat T, Kaur K (2015) Real-time detection of breast cancer cells using peptide-functionalized microcantilever arrays. Sci Rep 5:13967. https://doi.org/10.1038/srep13967
Ferrara N, Adamis AP (2016) Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov 15:385–403. https://doi.org/10.1038/nrd.2015.17
Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974. https://doi.org/10.1038/nature04483
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676. https://doi.org/10.1038/nm0603-669
Fiori N et al (2007) Structure-function relationship studies of PTH(1–11) analogues containing sterically hindered dipeptide mimetics. J Pept Sci 13:504–512. https://doi.org/10.1002/psc.872
Giordano RJ et al (2005) Structural basis for the interaction of a vascular endothelial growth factor mimic peptide motif and its corresponding receptors. Chem Biol 12:1075–1083. https://doi.org/10.1016/j.chembiol.2005.07.008
Giordano RJ et al (2010) From combinatorial peptide selection to drug prototype (I): targeting the vascular endothelial growth factor receptor pathway. Proc Natl Acad Sci USA 107:5112–5117. https://doi.org/10.1073/pnas.0915141107
Gongora-Benitez M, Tulla-Puche J, Albericio F (2014) Multifaceted roles of disulfide bonds. Peptides as therapeutics. Chem Rev 114:901–926. https://doi.org/10.1021/cr400031z
Guntert P (2004) Automated NMR structure calculation with CYANA. Methods Mol Biol 278:353–378
Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. J Phys Chem B 105:6474–6487. https://doi.org/10.1021/jp003919d
Kaumaya PT, Foy KC (2012) Peptide vaccines and targeting HER and VEGF proteins may offer a potentially new paradigm in cancer immunotherapy. Future Oncol 8:961–987. https://doi.org/10.2217/fon.12.95
Li YL, Zhao H, Ren XB (2016) Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol Med 13:206–214. https://doi.org/10.20892/j.issn.2095-3941.2015.0070
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7:359–371. https://doi.org/10.1038/nrm1911
Park S et al (2016) In vivo monitoring of angiogenesis in a mouse hindlimb ischemia model using fluorescent peptide-based probes. Amino Acids 48:1641–1654. https://doi.org/10.1007/s00726-016-2225-0
Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 92:905–909
Ponticelli S et al (2008) Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1. J Biol Chem 283:34250–34259. https://doi.org/10.1074/jbc.M806607200
Porto G et al (2011) Identification of novel immunoregulatory molecules in human thymic regulatory CD4+ CD25+ T cells by phage display. PLoS One 6:e21702. https://doi.org/10.1371/journal.pone.0021702
Rink R et al (2010) To protect peptide pharmaceuticals against peptidases. J Pharmacol Toxicol Methods 61:210–218. https://doi.org/10.1016/j.vascn.2010.02.010
Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114:853–865
Rusnati M, Presta M (2015) Angiogenic growth factors interactome and drug discovery: the contribution of surface plasmon resonance. Cytokine Growth Factor Rev 26:293–310. https://doi.org/10.1016/j.cytogfr.2014.11.007
Saito H, Tsujitani S, Ikeguchi M, Maeta M, Kaibara N (1998) Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer 78:1573–1577
Srabovic N, Mujagic Z, Mujanovic-Mustedanagic J, Softic A, Muminovic Z, Rifatbegovic A, Begic L (2013) Vascular endothelial growth factor receptor-1 expression in breast cancer and its correlation to vascular endothelial growth factor a. Int J Breast Cancer 2013:746749. https://doi.org/10.1155/2013/746749
Starzec A, Vassy R, Martin A, Lecouvey M, Di Benedetto M, Crepin M, Perret GY (2006) Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1. Life Sci 79:2370–2381. https://doi.org/10.1016/j.lfs.2006.08.005
Starzec A et al (2007) Structure-function analysis of the antiangiogenic ATWLPPR peptide inhibiting VEGF(165) binding to neuropilin-1 and molecular dynamics simulations of the ATWLPPR/neuropilin-1 complex. Peptides 28:2397–2402. https://doi.org/10.1016/j.peptides.2007.09.013
Tarallo V, De Falco S (2015) The vascular endothelial growth factors and receptors family: up to now the only target for anti-angiogenesis therapy. Int J Biochem Cell Biol 64:185–189. https://doi.org/10.1016/j.biocel.2015.04.008
Tugyi R, Uray K, Ivan D, Fellinger E, Perkins A, Hudecz F (2005) Partial d-amino acid substitution: improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide. Proc Natl Acad Sci USA 102:413–418. https://doi.org/10.1073/pnas.0407677102
Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718. https://doi.org/10.1002/jcc.20291
von Wronski MA et al (2006) Tuftsin binds neuropilin-1 through a sequence similar to that encoded by exon 8 of vascular endothelial growth factor. J Biol Chem 281:5702–5710. https://doi.org/10.1074/jbc.M511941200
Wizigmann-Voos S, Breier G, Risau W, Plate KH (1995) Up-regulation of vascular endothelial growth factor and its receptors in von Hippel–Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 55:1358–1364
Wuthrich K (1986) NMR of proteins and nucleic acids. Wiley, New York
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Research involving human participants and/or animals
The research program did not involve human participants or animals. No informed consent was therefore needed.
Additional information
Handling Editor: J. D. Wade.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Calvanese, L., Caporale, A., Focà, G. et al. Targeting VEGF receptors with non-neutralizing cyclopeptides for imaging applications. Amino Acids 50, 321–329 (2018). https://doi.org/10.1007/s00726-017-2519-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-017-2519-x