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VEGF-aptamer
Timeline
Used SELEX systematic evolution of ligands by exponential enrichment, to identify RNA ligands that bind to VEGF[1]
Used the SELEX process (systematic evolution of ligands by exponential enrichment), had isolated 2'-F-pyrimidine RNA oligonucleotide ligands (aptamers) to human VEGF165[3]
A nuclease-resistant, VEGF165-specific aptamer NX1838 (2'-fluoropyrimidine, RNA-based oligonucleotide/40-kDa-PEG) was developed[4]
Comparison of NMR spectra revealed that structural features of the smaller HBD-aptamer complex are present in the full-length VEGF(164)-aptamer complex[7]
A review about Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer) is an RNA aptamer directed against vascular endothelial growth factor (VEGF)-165[8]
Reported that both streptozotocin (STZ)-induced diabetes in rats and Macugen intravitreal injection in mice leads to retinal apoptosis in retinal ganglion cell and outer nuclear layers respectively[15]
A time-resolved chemiluminescence enzyme-linked aptamer assay was developed for the simultaneous detections of CEA and VEGF in serum samples[16]
Description
In 1994, Jellinek, D. et al. used SELEX to identify RNA ligands that bind to VEGF in a specific manner with affinities in the low nanomolar range. In 1995, followed by the use of F-substituted nucleotides to further improve affinity. In 1998, three stable, high-affinity candidate anti-VEGF aptamers were characterized. In 1999, Pegaptanib was further characterized in experiments with cultured endothelial cells. In subsequent work, pegaptanib was found to be stable in human plasma at ambient temperatures for more than 18 hours, dthe pharmacokinetics of pegaptanib were evaluated following in rhesus monkeys. In 2004, The safety and efficacy of pegaptanib in the treatment of choroidal neovascularization secondary to AMD were tested in two clinical trials.In December 2004, the US FDA approved pegaptanib sodium (Macugen), an anti-vascular endothelial growth factor (anti-VEGF) RNA aptamer, for the treatment of all types of neovascular age-related macular degeneration (AMD)[1,2,3,4,5,6].SELEX
Random RNA used in the initial selection bound to VEGF with an affinity of approximately 0.2 pM. After 13 rounds of SELEX, the observed improvement in affinity of the evolved RNA pool was about 2 orders of magnitude. Cloned and sequenced 64 isolates from this evolved pool and found 37 unique sequences. In 1998, Janjić, N. et al isolated 2'-F-pyrimidine RNA oligonucleotide ligands (aptamers) to human VEGF165. Aptamers to VEGF165 were isolated in three separate SELEX experiments from 2′-F-pyrimidine RNA libraries containing 30 or 40 random nucleotides. After 10 cycles, the affinity between VEGF and each RNA pool had improved approximately 1000-fold relative to the starting pools (data not shown). individual members of the 12th round pools were cloned and sequences were determined for about 50 isolates from each selection[1,3].
Detailed information are accessible on SELEX page.
Structure
The 2D structure of the figures is based on the article by ribodraw tool to draw[3].5'-GCGGAAUCAGUGAAUGCUUAUACAUCCGC-3'
Ligand information
SELEX ligand
Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF),is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).-----From Wiki
| Name | Uniprot ID | Pfam | MW | Amino acids sequences | PDB | Gene ID |
|---|---|---|---|---|---|---|
| Vascular endothelial growth factor(VEGF) heparin-binding domain | P15692 | PF14554 | 6.48 KDa | ARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR | 1VGH | 7422 |
Some isolated sequences bind to the affinity of the protein.
| Name | Sequence | Ligand | Affinity |
|---|---|---|---|
| t22-OMe aptamer | 5'-GCGGUAGGAAGAAUUGGAAGCGC-3' | Vascular endothelial growth factor(VEGF) | 72±11 pM |
| t2-OMe aptamer | 5'-GCGAACCGAUGGAAUUUUUGGACGCUCGC-3' | Vascular endothelial growth factor(VEGF) | 113±19 pM |
| t44-OMe aptamer | 5'-CGGAAUCAGUGAAUGCUUAUACAUCCG-3' | Vascular endothelial growth factor(VEGF) | 49±6 pM |
Similar compound
We used the Dail server website to compare the structural similarities of ligand proteins, and chose the top 10 in terms of similarity for presentation. The Dali server is a network service for comparing protein structures in 3D. Dali compares them against those in the Protein Data Bank (PDB). Z-score is a standard score that is converted from an original score. The list of neighbours is sorted by Z-score. Similarities with a Z-score lower than 2 are spurious. RMSD(Root Mean Square Deviation) value is used to measure the degree to which atoms deviate from the alignment position.
| PDB | Z-socre | RMSD | Description |
|---|---|---|---|
| 2VGH-A | 11.3 | 0.0 | vascular endothelial growth factor-165 |
| 1VGH-A | 7.9 | 2.3 | vascular endothelial growth factor-165 |
| 1KMX-A | 7.0 | 1.9 | vascular endothelial growth factor |
| 4DEQ-B | 6.1 | 2.5 | neuropilin-1, vascular endothelial growth |
| 4DEQ-A | 6.0 | 2.7 | neuropilin-1, vascular endothelial growth |
References
[1] Inhibition of receptor binding by high-affinity RNA ligands to vascular endothelial growth factor.Jellinek, D., Green, L. S., Bell, C., & Janjić, N.
Biochemistry, 33(34), 10450–10456. (1994)
[2] Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor.
Green, L. S., Jellinek, D., Bell, C., Beebe, L. A., Feistner, B. D., Gill, S. C., Jucker, F. M., & Janjić, N.
Chemistry & biology, 2(10), 683–695. (1995)
[3] 2'-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain.
Ruckman, J., Green, L. S., Beeson, J., Waugh, S., Gillette, W. L., Henninger, D. D., Claesson-Welsh, L., & Janjić, N.
The Journal of biological chemistry, 273(32), 20556–20567. (1998)
[4] Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro.
Bell, C., Lynam, E., Landfair, D. J., Janjic, N., & Wiles, M. E.
In vitro cellular & developmental biology. Animal, 35(9), 533–542. (1999)
[5] Detection and plasma pharmacokinetics of an anti-vascular endothelial growth factor oligonucleotide-aptamer (NX1838) in rhesus monkeys.
Tucker, C. E., Chen, L. S., Judkins, M. B., Farmer, J. A., Gill, S. C., & Drolet, D. W.
Journal of chromatography. B, Biomedical sciences and applications, 732(1), 203–212. (1999)
[6] Pegaptanib for neovascular age-related macular degeneration.
Gragoudas, E. S., Adamis, A. P., Cunningham, E. T., Jr, Feinsod, M., Guyer, D. R., & VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group
The New England journal of medicine, 351(27), 2805–2816. (2004)
[7] A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165.
Lee, J. H., Canny, M. D., De Erkenez, A., Krilleke, D., Ng, Y. S., Shima, D. T., Pardi, A., & Jucker, F.
Proceedings of the National Academy of Sciences of the United States of America, 102(52), 18902–18907. (2005)
[8] Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease.
Ng, E. W., Shima, D. T., Calias, P., Cunningham, E. T., Jr, Guyer, D. R., & Adamis, A. P.
Nature reviews. Drug discovery, 5(2), 123–132. (2006)
[9] Development of the anti-VEGF aptamer to a therapeutic agent for clinical ophthalmology.
Trujillo, C. A., Nery, A. A., Alves, J. M., Martins, A. H., & Ulrich, H.
Clinical ophthalmology (Auckland, N.Z.), 1(4), 393–402. (2007)
[10] Wirkung von VEGF165 und dem VEGF-Aptamer Pegaptanib (Macugen) auf die Zusammensetzung der Tight Junctions mikrovaskulärer Endothelzellen aus der Retina [Effect of VEGF165 and the VEGF aptamer pegaptanib (Macugen) on the protein composition of tight junctions in microvascular endothelial cells of the retina].
Deissler, H. L., & Lang, G. E.
Klinische Monatsblatter fur Augenheilkunde, 225(10), 863–867. (2008)
[11] Intraocular pressure effects of pegaptanib (macugen) injections in patients with and without glaucoma.
Lanzl, I. M., Maier, M., Feucht, N., Lohmann, C. P., & Kotliar, K. E.
American journal of ophthalmology, 145(1), 185–186. (2008)
[12] Combined Pegaptanib sodium (Macugen) and photodynamic therapy in predominantly classic juxtafoveal choroidal neovascularisation in age related macular degeneration.
Calvo-González, C., Reche-Frutos, J., Donate-López, J., García-Feijoó, J., Leila, M., Fernández-Pérez, C., & Garcia-Sánchez, J.
The British journal of ophthalmology, 92(1), 74–75. (2008)
[13] Development of an aptamer-based affinity purification method for vascular endothelial growth factor.
Lönne, M., Bolten, S., Lavrentieva, A., Stahl, F., Scheper, T., & Walter, J. G.
Biotechnology reports (Amsterdam, Netherlands), 8, 16–23. (2015)
[14] Population pharmacokinetics of pegaptanib sodium (Macugen(®)) in patients with diabetic macular edema.
Basile, A. S., Hutmacher, M. M., Kowalski, K. G., Gandelman, K. Y., & Nickens, D. J.
Clinical ophthalmology (Auckland, N.Z.), 9, 323–335. (2015)
[15] VEGF-B inhibits hyperglycemia- and Macugen-induced retinal apoptosis.
Huang, D., Zhao, C., Ju, R., Kumar, A., Tian, G., Huang, L., Zheng, L., Li, X., Liu, L., Wang, S., Ren, X., Ye, Z., Chen, W., Xing, L., Chen, Q., Gao, Z., Mi, J., Tang, Z., Wang, B., Zhang, S., … Li, X.
Scientific reports, 6, 26059. (2016)
[16] Simultaneous Detection of VEGF and CEA by Time-Resolved Chemiluminescence Enzyme-Linked Aptamer Assay.
Man, J., Dong, J., Wang, Y., He, L., Yu, S., Yu, F., Wang, J., Tian, Y., Liu, L., Han, R., Guo, H., Wu, Y., & Qu, L.
International journal of nanomedicine, 15, 9975–9985. (2020)
[17] VEGF aptamer/i-motif-based drug co-delivery system for combined chemotherapy and photodynamic therapy.
Zhao, P., Tang, Z. W., Lin, H. C., Djuanda, D., Zhu, Z., Niu, Q., Zhao, L. M., Qian, Y. N., Cao, G., Shen, J. L., & Fu, B.
Photodiagnosis and photodynamic therapy, 36, 102547. (2021)
[18] Molecular mechanism of binding between a therapeutic RNA aptamer and its protein target VEGF: A molecular dynamics study.
Kalathingal, M., & Rhee, Y. M.
Journal of computational chemistry, 44(11), 1129–1137. (2023)