Skip to main content

Design and Biological Application of RTK Agonist Aptamers

  • Living reference work entry
  • First Online:
Handbook of Chemical Biology of Nucleic Acids
  • 79 Accesses

Abstract

Growth factors (GFs) play important roles in cell–cell communication by transducing cell signaling through binding to receptor tyrosine kinases (RTKs), single-pass transmembrane receptors with kinase activity. GF stimulates various cellular activities, such as proliferation, migration, and differentiation, to secure the developmental process and maintain tissue homeostasis. Owing to the regenerative action, recombinant GFs have been widely used in the treatment of disease and injured tissue. In addition, GF is supplemented in culture media to control cellular activity in vitro. However, recombinant GFs often suffer from their limitations such as high production cost, risk of contamination, and batch-to-batch activity variations. Aptamers are single-stranded oligonucleotides with molecular recognition ability that have attracted attention as a promising alternative. They can bind to target molecules with high affinity and specificity, which are often comparable to those of antibodies. RTK-binding aptamer can be generated through a well-established molecular evolution process called “systematic evolution of ligands by exponential enrichment” (SELEX) using a purified extracellular domain of receptor or receptor expressing cells. This chapter summarizes the RTK-binding aptamers and their applications in the modulation of RTK activity, particularly focusing on the generation and rational design of agonist aptamer to RTKs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

References

  • Akiyama M, Ueki R, Yanagawa M et al (2021) DNA-based synthetic growth factor surrogates with fine-tuned agonism. Angew Chem Int Ed 60:22745–22752

    Google Scholar 

  • Apte RS, Chen DS, Ferrara N (2019) VEGF in signaling and disease: beyond discovery and development. Cell 176:1248–1264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berezovski MV, Musheev MU, Drabovich AP et al (2006) Non-SELEX: selection of aptamers without intermediate amplification of candidate oligonucleotides. Nat Protoc 1:1359–1369

    Article  CAS  PubMed  Google Scholar 

  • Birchmeier C, Birchmeier W, Gherardi E et al (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925

    Article  CAS  PubMed  Google Scholar 

  • Boltz A, Piater B, Toleikis L et al (2011) Bi-specific aptamers mediating tumor cell lysis. J Biol Chem 286:21896–21905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brigadski T, Leßmann V (2014) BDNF: a regulator of learning and memory processes with clinical potential. e-Neuroforum 5:1–11

    Google Scholar 

  • Burmeister PE, Lewis SD, Silva RF et al (2005) Direct in vitro selection of a 2′-O-methyl aptamer to VEGF. Chem Biol 12:25–33

    Article  CAS  PubMed  Google Scholar 

  • Camorani S, Crescenzi E, Fedele M et al (2018) Oligonucleotide aptamers against tyrosine kinase receptors: prospect for anticancer applications. Biochim Biophys Acta Rev Cancer 1869:263–277

    Article  CAS  PubMed  Google Scholar 

  • Dimitrov DS (2012) Therapeutic proteins. Methods Mol Biol 899:1–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ellington AD, Szostak JW (1990) In vitro selection of RNA molecules that bind specific ligands. Nature 346:818–822

    Article  CAS  PubMed  Google Scholar 

  • Fan J, Wang H-H, Xie S et al (2020) Engineering cell-surface receptors with DNA nanotechnology for cell manipulation. Chembiochem 21:282–293

    Article  CAS  PubMed  Google Scholar 

  • Fang RC, Galiano RD (2008) A review of becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Biologics 2:1–12

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gherardi E, Birchmeier W, Birchmeier C et al (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12:89–103

    Article  CAS  PubMed  Google Scholar 

  • Gold L, Ayers D, Bertino J et al (2010) Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One 5:e15004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta S, Hirota M, Waugh SM et al (2014) Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor. J Biol Chem 289:8706–8719

    Google Scholar 

  • Haeusler RA, McGraw TE, Accili D (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31–44

    Article  CAS  PubMed  Google Scholar 

  • Ho CCM, Chhabra A, Starkl P et al (2017) Decoupling the functional pleiotropy of stem cell factor by tuning c-kit signaling. Cell 168:1041–1052.e18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoshiyama J, Okada Y, Hayata Y et al (2021) Characterization of a DNA aptamer with high specificity toward fibroblast growth factor receptor 1. Chem Lett 50:1949–1952

    Google Scholar 

  • Huang YZ, Hernandez FJ, Gu B et al (2012) RNA aptamer-based functional ligands of the neurotrophin receptor, TrkB. Mol Pharmacol 82:623–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hubbard SR (2013) Structural biology: insulin meets its receptor. Nature 493:171–172

    Google Scholar 

  • Ito K, Sakai K, Suzuki Y et al (2015) Artificial human Met agonists based on macrocycle scaffolds. Nat Commun 6:6373

    Article  CAS  PubMed  Google Scholar 

  • Jurek PM, Zabłocki K, Waśko U et al (2017) Anti-FGFR1 aptamer-tagged superparamagnetic conjugates for anticancer hyperthermia therapy. Int J Nanomedicine 12:2941–2950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamatkar N, Levy M, Hébert JM (2019) Development of a monomeric inhibitory RNA aptamer specific for FGFR3 that acts as an activator when dimerized. Mol Ther Nucleic Acids 17:530–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katoh M (2016) Therapeutics targeting FGF signaling network in human diseases. Trends Pharmacol Sci 37:1081–1096

    Article  CAS  PubMed  Google Scholar 

  • Keefe AD, Pai S, Ellington A (2010) Aptamers as therapeutics. Nat Rev Drug Discov 9:537–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lawrence MC (2021) Understanding insulin and its receptor from their three-dimensional structures. Mol Metab 52:101255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levenstein ME, Ludwig TE, Xu R-H et al (2006) Basic fibroblast growth factor support of human embryonic stem cell self-renewal. Stem Cells 24:568–574

    Google Scholar 

  • Matsumoto K, Funakoshi H, Takahashi H et al (2014) HGF-Met pathway in regeneration and drug discovery. Biomedicines 2:275–300

    Article  PubMed  PubMed Central  Google Scholar 

  • Mendonsa SD, Bowser MT (2004) In vitro evolution of functional DNA using capillary electrophoresis. J Am Chem Soc 126:20–21

    Article  CAS  PubMed  Google Scholar 

  • Menting JG, Whittaker J, Margetts MB et al (2013) How insulin engages its primary binding site on the insulin receptor. Nature 493:241–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchell AC, Briquez PS, Hubbell JA et al (2016) Engineering growth factors for regenerative medicine applications. Acta Biomater 30:1–12

    Article  CAS  PubMed  Google Scholar 

  • Moraga I, Wernig G, Wilmes S et al (2015) Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. Cell 160:1196–1208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ng EWM, Shima DT, Calias P et al (2006) Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 5:123–132

    Article  CAS  PubMed  Google Scholar 

  • Niemann HH (2013) Structural basis of MET receptor dimerization by the bacterial invasion protein InlB and the HGF/SF splice variant NK1. Biochim Biophys Acta 1834:2195–2204

    Article  CAS  PubMed  Google Scholar 

  • Padilla R, Sousa R (1999) Efficient synthesis of nucleic acids heavily modified with non-canonical ribose 2′-groups using a mutant T7 RNA polymerase (RNAP). Nucleic Acids Res 27:1561–1563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piater B, Doerner A, Guenther R et al (2015) Aptamers binding to c-Met inhibiting tumor cell migration. PLoS One 10:e0142412

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramaswamy V, Monsalve A, Sautina L et al (2015) DNA aptamer assembly as a vascular endothelial growth factor receptor agonist. Nucleic Acid Ther 25:227–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlessinger J, Plotnikov AN, Ibrahimi OA et al (2000) Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell 6:743–750

    Article  CAS  PubMed  Google Scholar 

  • Sefah K, Shangguan D, Xiong X et al (2010) Development of DNA aptamers using cell-SELEX. Nat Protoc 5:1169–1185

    Article  CAS  PubMed  Google Scholar 

  • Shaw A, Lundin V, Petrova E et al (2014) Spatial control of membrane receptor function using ligand nanocalipers. Nat Methods 11:841–846

    Article  CAS  PubMed  Google Scholar 

  • Shibuya M (2011) Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2:1097–1105

    Article  PubMed  PubMed Central  Google Scholar 

  • Simonneau C, Leclercq B, Mougel A et al (2015) Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist. Chem Sci 6:2110–2121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simons M, Gordon E, Claesson-Welsh L (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17:611–625

    Article  CAS  PubMed  Google Scholar 

  • Sonoda J, Chen MZ, Baruch A (2017) FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases. Horm Mol Biol Clin Investig 30. https://doi.org/10.1515/hmbci-2017-0002

  • Tang JY, Temsamani J, Agrawal S (1993) Self-stabilized antisense oligodeoxynucleotide phosphorothioates: properties and anti-HIV activity. Nucleic Acids Res 21:2729–2735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tolbert WD, Daugherty J, Gao C et al (2007) A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist. Proc Natl Acad Sci U S A 104:14592–14597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tolbert WD, Daugherty-Holtrop J, Gherardi E et al (2010) Structural basis for agonism and antagonism of hepatocyte growth factor. Proc Natl Acad Sci U S A 107:13264–13269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505–510

    Article  CAS  PubMed  Google Scholar 

  • Ueki R, Sando S (2014) A DNA aptamer to c-Met inhibits cancer cell migration. Chem Commun 50:13131–13134

    Article  CAS  Google Scholar 

  • Ueki R, Ueki A, Kanda N et al (2016) Oligonucleotide-based mimetics of hepatocyte growth factor. Angew Chem Int Ed 5:579–582

    Google Scholar 

  • Ueki R, Atsuta S, Ueki A et al (2019) DNA aptamer assemblies as fibroblast growth factor mimics and their application in stem cell culture. Chem Commun 55:2672–2675

    Article  CAS  Google Scholar 

  • Ueki R, Uchida S, Kanda N et al (2020) A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application. Sci Adv 6:eaay2801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vaught JD, Bock C, Carter J et al (2010) Expanding the chemistry of DNA for in vitro selection. J Am Chem Soc 132:4141–4151

    Article  CAS  PubMed  Google Scholar 

  • Wang M, He F, Li H et al (2019) Near-infrared light-activated DNA-agonist nanodevice for nongenetically and remotely controlled cellular signaling and behaviors in live animals. Nano Lett 19:2603–2613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang S, Zhao J, Sun X (2016) Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. Drug Des Devel Ther 10:1857–1867

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yip CC, Ottensmeyer P (2003) Three-dimensional structural interactions of insulin and its receptor. J Biol Chem 278:27329–27332

    Article  CAS  PubMed  Google Scholar 

  • Yoshitomi T, Hayashi M, Oguro T et al (2020) Binding and structural properties of DNA aptamers with VEGF-A-mimic activity. Mol Ther Nucleic Acids 19:1145–1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshizawa S, Ueda T, Ishido Y et al (1994) Nuclease resistance of an extraordinarily thermostable mini-hairpin DNA fragment, d(GCGAAGC) and its application to in vitro protein synthesis. Nucleic Acids Res 22:2217–2221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yunn N-O, Koh A, Han S et al (2015) Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation. Nucleic Acids Res 43:7688–7701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yunn N-O, Park M, Park S et al (2021) A hotspot for enhancing insulin receptor activation revealed by a conformation-specific allosteric aptamer. Nucleic Acids Res 49:700–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuzawa S, Opatowsky Y, Zhang Z et al (2007) Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell 130:323–334

    Article  CAS  PubMed  Google Scholar 

  • Zahavi EE, Steinberg N, Altman T et al (2018) The receptor tyrosine kinase TrkB signals without dimerization at the plasma membrane. Sci Signal 11:eaao4006

    Google Scholar 

  • Zhang K, Gao H, Deng R et al (2019) Emerging applications of nanotechnology for controlling cell-surface receptor clustering. Angew Chem Int Ed 58:4790–4799

    Article  CAS  Google Scholar 

  • Zhou J, Rossi J (2017) Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov 16:181–202

    Google Scholar 

  • Zhu Q, Liu G, Kai M (2015) DNA aptamers in the diagnosis and treatment of human diseases. Molecules 20:20979–20997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ryosuke Ueki or Shinsuke Sando .

Editor information

Editors and Affiliations

Section Editor information

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Singapore Pte Ltd.

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Ueki, R., Sando, S. (2022). Design and Biological Application of RTK Agonist Aptamers. In: Sugimoto, N. (eds) Handbook of Chemical Biology of Nucleic Acids. Springer, Singapore. https://doi.org/10.1007/978-981-16-1313-5_78-1

Download citation

  • DOI: https://doi.org/10.1007/978-981-16-1313-5_78-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-16-1313-5

  • Online ISBN: 978-981-16-1313-5

  • eBook Packages: Springer Reference Chemistry and Mat. ScienceReference Module Physical and Materials ScienceReference Module Chemistry, Materials and Physics

Publish with us

Policies and ethics