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1 Bivalent and multivalent aptamers are very promising and versatile tools with potential applications as anticoagulants therapeutics. The set of newly designed highly effective multivalent aptamers will certainly be enriched in the foreseeable future..
Claudia Riccardi
 + 2007 word(s) 2007 2020-11-19 09:22:37 |
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Catherine Yang
 Meta information modification 2007 2020-11-30 04:26:52 | |
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Catherine Yang
 Meta information modification 2007 2020-12-01 07:26:11 |

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Riccardi, C.; Napolitano, E.; Musumeci, D.; Montesarchio, D. Dimeric/Multimeric Anticoagulant DNA Aptamers. Encyclopedia. Available online: https://encyclopedia.pub/entry/3266 (accessed on 19 April 2024).
Riccardi C, Napolitano E, Musumeci D, Montesarchio D. Dimeric/Multimeric Anticoagulant DNA Aptamers. Encyclopedia. Available at: https://encyclopedia.pub/entry/3266. Accessed April 19, 2024.
Riccardi, Claudia, Ettore Napolitano, Domenica Musumeci, Daniela Montesarchio. "Dimeric/Multimeric Anticoagulant DNA Aptamers" Encyclopedia, https://encyclopedia.pub/entry/3266 (accessed April 19, 2024).
Riccardi, C., Napolitano, E., Musumeci, D., & Montesarchio, D. (2020, November 27). Dimeric/Multimeric Anticoagulant DNA Aptamers. In Encyclopedia. https://encyclopedia.pub/entry/3266
Riccardi, Claudia, et al. "Dimeric/Multimeric Anticoagulant DNA Aptamers." Encyclopedia. Web. 27 November, 2020.
Dimeric/Multimeric Anticoagulant DNA Aptamers
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This entry is adapted from the peer-reviewed paper 10.3390/molecules25225227

Multivalent interactions frequently occur in biological systems and typically provide higher binding affinity and selectivity in target recognition than when only monovalent interactions are operative. Thus, taking inspiration by nature, bivalent or multivalent nucleic acid aptamers recognizing a specific biological target have been extensively studied in the last decades. Indeed, oligonucleotide-based aptamers are suitable building blocks for the development of highly efficient multivalent systems since they can be easily modified and assembled exploiting proper connecting linkers of different nature. Thus, substantial research efforts have been put in the construction of dimeric/multimeric versions of effective aptamers with various degrees of success in target binding affinity or therapeutic activity enhancement. Several dimeric and multimeric DNA-based aptamers, including those forming G-quadruplex (G4) structures, were designed as anti-inflammatory, antiviral, anticoagulant, and anticancer agents and their number is certainly bound to grow in the near future. In this content, we here focus on dimeric/multimeric constructs designed as anticoagulant agents.

aptamer G-quadruplex design dimerization multivalency molecular recognition protein target therapy

1. Introduction

Nucleic acid-based aptamers are short single-stranded DNA or RNA molecules which, upon folding in their peculiar three-dimensional structure, can bind with high affinity and specificity a selected target of biological interest. They are also called “chemical antibodies”, but compared to protein-based molecules, oligonucleotide aptamers generally show lower immunogenicity, higher stability in a wide range of pH and temperature and the possibility to be differently modified or conjugated. Indeed, site-specific chemical modifications can be easily inserted in oligonucleotide aptamers to improve their stability to nuclease digestion or modulate binding affinity to their target [1][2][3][4][5][6]. These intriguing properties make oligonucleotide aptamers very attractive tools in both therapeutic [2][7][8][9][10][11][12][13][14][15] and diagnostic [16][17][18][19][20][21][22] applications [23].

Starting from a large pool of random oligonucleotide sequences, high affinity aptamers for a given target are generally identified through an in vitro selection process named Systematic Evolution of Ligands by Exponential Enrichment (SELEX) [24][25]. The outstanding progress achieved in this field resulted in a variety of selection methods and a large number of aptamers specific for very different kinds of targets—from small molecules, ions, proteins, cells, to even whole organisms, such as viruses or bacteria—have been thus far fished out [26][27][28][29][30][31][32].

Moreover, several aptamers are specifically internalized upon binding to cell membrane receptors and thus can serve as ideal selective delivery systems for different therapeutic targets, from small, conventional drugs to microRNAs or small interfering RNAs (siRNAs) [10][33][34].

Notably, among combinatorially selected aptamers, most of the oligonucleotides endowed with valuable biological activity are able to adopt stem-loop or G-quadruplex (G4) structures. The simplest architecture is represented by the stem-loop or hairpin rearrangement, i.e., an intramolecular conformation based on the coupling of complementary nucleobases in a single-stranded DNA sequence [35].

In contrast, oligonucleotides featured by guanine-rich sequences generally share the ability to fold into peculiar G4 structures [36][37][38][39][40]. The central core of a G4 architecture is the G-tetrad, a structural motif also named G-quartet, which consists of a cyclic planar arrangement of four guanine bases associated through Hoogsteen-type hydrogen bonds [38][40][41][42][43]. Stacking of two or more G-tetrads provides central cavities with a strong negative electrostatic potential, in which cations can be well accommodated, strongly influencing the formation, stability, and topology of the resulting G4 structure [44][45][46][47].

Considering that protein targets involved in specific diseases can (i) have more than one potential binding site recognized by different aptamers, (ii) be dimeric, tetrameric, or in general multimeric, (iii) dimerize or multimerize as a consequence of physiological or pathological events, multivalent aptamer constructs, especially in the simple dimeric forms, are of particular interest [48][49][50][51]. Specifically, a multivalent aptamer is a construct composed of two or more units of the same or different aptamer motifs, containing or not additional structural elements or functional linkers, able to interact simultaneously with more protein binding sites, generally improving its overall efficacy.

Remarkably, SELEX often identifies oligonucleotide aptamers with a repeated sequence, suggesting high affinity recognition ability by dimeric aptamers for a given protein. As an alternative, since aptamers are largely amenable to chemical modifications [1][2][3][4][5][6], the oligonucleotide sequences initially discovered by SELEX can be easily modified to give dimeric or multimeric aptamers without linkers or using proper spacers of different nature (nucleotidic or not), length and flexibility, and exploiting different kinds of connecting interactions (base-pairs recognitions, covalent chemical linkages). Therefore, oligonucleotide aptamers represent a rich arsenal of finely tunable building blocks, which can be profitably joined to generate suitable constructs with improved functions and properties.

Most exploited strategies involve the simple combination of two of more aptamer units concurrently binding two different domains of a target protein with key biological functions in physiological and pathological conditions.

Dimeric and multimeric DNA-based aptamers were developed as therapeutic tools targeting key proteins in different relevant diseases, such as inflammation, viral infection, thrombosis and cancer.https://www.mdpi.com/1420-3049/25/22/5227

We here describe the selection, design and properties of anti-thrombin multivalent DNA-based aptamers in terms of binding affinity and/or therapeutic efficacy.

2. Anticoagulant Aptamers

The most popular protein target for anticoagulant therapies is thrombin, a multifunctional “trypsin-like” serine protease able to bind fibrinogen and thus catalyze its conversion to fibrin clots in the last step of blood coagulation [52][53][54][55][56][57]. Considering its pivotal role in the coagulation cascade, the inhibition of thrombin activity is one of the most efficient antithrombotic strategies [58][59][60][61]. In this context, the development of effective antithrombin aptamers has been the focus of several investigations [61][62][63][64][65].

The most popular antithrombin aptamers able to inhibit thrombin activity are TBA15, TBA29, and TBA27 [61][65]. Besides differing for their overall length, these aptamers show distinct three-dimensional structures and recognize different thrombin binding sites [65].
Indeed, TBA29 and TBA27—also known as HD22-29 and HD22-27—adopt a mixed duplex/G4 architecture able to bind the exosite II of thrombin (heparin-binding site or ABE II) with high affinity (Kd values of 0.5 and 0.7 nM, respectively for TBA29 and TBA27) [66][67]. In particular, TBA27 is a truncated form of TBA29 (5'-AGTCCGTGGTAGGGCAGGTTGGGGTGACT-3') lacking the first and last residue of the parent aptamer. In contrast, TBA15 or simply TBA, of sequence 5'-GGTTGGTGTGGTTGG-3', folds into a stable chair-like, antiparallel G4 structure able to inhibit the conversion of soluble fibrinogen into insoluble fibrin strands by binding to thrombin exosite I (fibrinogen-binding site or ABE I) with a Kd of 26 nM [65][66][67][68][69][70][71][72][73][74][75].
Starting from these G-rich oligomers, several homo and heterodimeric constructs were developed as effective antithrombin agents [48][66].
RA-36 is the simplest TBA-based homodimeric aptamer. This 31-mer oligonucleotide comprises two TBA15 units, both in 5'-3' direction, covalently linked through one thymidine residue at position 16. As its monomeric precursor, RA-36 recognizes thrombin exosite I, inhibiting the binding between the protein and fibrinogen [76]. Notably, this dimer was able to exert its activity only in a K+-rich solution, suggesting that the formation of a stable G4 structure is strictly required for effective inhibition of thrombin catalytic action [76][77].
The intriguing properties of RA-36 stimulated the design of other dimeric TBA15 variants, obtained by joining the 3'-ends of each G4 module and introducing inversion of polarity sites in the overall sequence. The connection between TBA15 motifs was realized using various symmetric linkers—i.e., deoxyadenosine or thymidine residues and/or a glycerol moiety—in place of the thymidine at position 16. Unfortunately, the direct comparison of the anticoagulant properties of the newly developed derivatives with the parent RA-36 was not performed, but the evaluation of prothrombin times revealed improved anticoagulant activity and higher Tm values for most of the designed dimers, compared to unmodified TBA15 [78].
Alternative dimeric constructs were based on the covalent connection between TBA15 and other antithrombin aptamers providing heterodimers able to recognize different thrombin exosites.
In particular, TBA15 and TBA29 were linked exploiting different spacers, such as a 15-nucleotide long poly(dA) linker providing HD1-22 [79][80] or poly(T) spacers of various length [81].
In all cases, TBA15/TBA29 dimeric derivatives showed improved thrombin affinity and/or inhibition activity with respect to each monovalent parent aptamer, especially when a poly(T) spacer of 5 residues was explored [79][80][81].
In a different approach, the same aptamers were joined by ethylene glycol spacers of different length. For instance, Tian and Heyduk prepared a covalent dimer of TBA15 and TBA29 featured by flexible connections based on 5'-(OCH2CH2)6-OPO3-3' (spacer 18) repeated 5 or 10 times [82]. Five repeated units of the spacer provided an overall linker length of 12 nm, while 10 repetitions allowed reaching a 24 nm-long spacer. This longer version was used both to link the 3'-end of TBA29 with the 5'-end of TBA15 and vice versa. In all cases, the designed bivalent analogues proved to be more efficient in terms of thrombin binding affinity than the starting monomeric aptamers [82].
In turn, Hughes et al. inserted an inverted thymidine (iT) at the 3'-end position of TBA15 and TBA29, thus providing RNV216A and RNV219, respectively [83]. These modified versions were then linked by using either a triethylene glycol (TEG) spacer (RNV220) or four thymidine residues (RNV220-T). Compared to both monovalent aptamers, RNV220 and RNV220-T showed significantly improved antithrombin activity in blood plasma [83].
As a valuable alternative to rational design, Ahmad and coworkers used an in vitro selection strategy to identify the optimal sequence joining TBA15 and TBA29 motifs. The randomized linker was 35-nucleotide long, covering the distance between the different thrombin binding exosites [84]. The resulting 119-mer bivalent aptamer (TBV-08) exhibited noteworthy thrombin binding affinity in the picomolar range (Kd of 8.1 pM) which well correlated with improved antithrombin activity. Similarly to previous approaches, the authors also prepared bivalent constructs presenting poly(T) or poly(dA) linkers. Interesting results in terms of Kd values were also found for the dimer containing a poly(T) spacer of 16 residues [84].
Only one study reported the covalent connection of TBA15 and the shorter HD22 aptamer, i.e., TBA27. In detail, from 2 to 10 units of the commercially available hexaethylene glycol (HEG)-based phosphoramidite were inserted to join the different monomeric aptamer units. The best results in terms of thrombin inhibitory activity were found for the analogue including 8 repeated units of the linker phosphoramidite 18, corresponding to a length of ca. 16 nm [85]. On the contrary, introduction of the shortest spacer of the series, i.e., the one constituted by 4 repeated units of phosporamidite 18, dramatically reduced the inhibitory activity of the obtained dimer analogue [85].
In order to simultaneously increase the resistance to nuclease degradation and the thrombin binding properties, Di Giusto and colleagues proposed circular multivalent constructs [86][87]. Indeed, circularization is a well-established strategy to improve the performance of aptamers [88][89] and has been efficiently applied to antithrombin aptamers targeting thrombin exosite I [66][90][91][92].
In this work, four different DNA aptamers were exploited as building blocks to obtain circular multivalent constructs: antithrombin aptamers TBA29 and GS-522 (i.e., a 15-mer with the sequence 5'-GGTTGGTGAGGTTGG-3' able to bind thrombin exosite I [68] ), the L-selectin aptamer [93] and the aptamer against red blood cell marker. A DNA hairpin loop was included as an ancillary module between the aptamer motifs and all the resulting oligonucleotides were also elongated with flanking regions to allow extended stem-loop structure formation. Intra- or intermolecular DNA ligation approaches were used to provide each multivalent circular species, which finally involved two, three or four identical or different aptamer units [86]. The circular multivalent aptamers showed noteworthy stability in both serum and plasma along with improved anticoagulant activity compared to each parent antithrombin aptamer [86].

Another strategy to generate homo- or heteromultimers of a selected aptamer is based on the use of suitable nanoplatforms on which multiple copies of the monomeric aptamer can be linked [48]. This approach has been extensively investigated for TBA15, which thanks to its short sequence and well-known three-dimensional structure, well conserved also when bound to thrombin [94][95], is often exploited as a model system in proof-of-concept studies [48].

In this context, TBA15 was incorporated onto very different nanoplatforms, including magnetic [96][97][98], gold [99][100][101][102][103], silica-based nanoparticles [104][105][106][107], and graphene [108][109]. As a remarkable example, Hsu et al. proposed the multimerization of both TBA15 and TBA29 on the surface of gold nanoparticles (AuNPs). To reach this aim, both aptamers were equipped with thiol end groups allowing their attachment onto the gold surface through Au-thiol interactions [101]. The resulting multivalent nanoparticles, functionalized with about 15 molecules of each aptamer, exhibited an exceptionally high binding affinity for thrombin with a Kd value of 3.4 fM [101].

References

  1. Wang, R.E.; Wu, H.; Niu, Y.; Cai, J. Improving the stability of aptamers by chemical modification. Curr. Med. Chem. 2011, 18, 4126–4138.
  2. Yu, Y.; Liang, C.; Lv, Q.; Li, D.; Xu, X.; Liu, B.; Lu, A.; Zhang, G. Molecular selection, modification and development of therapeutic oligonucleotide aptamers. Int. J. Mol. Sci. 2016, 17, 358.
  3. Ni, S.; Yao, H.; Wang, L.; Lu, J.; Jiang, F.; Lu, A.; Zhang, G. Chemical modifications of nucleic acid aptamers for therapeutic purposes. Int. J. Mol. Sci. 2017, 18, 1683.
  4. Röthlisberger, P.; Hollenstein, M. Aptamer chemistry. Adv. Drug Deliv. Rev. 2018, 134, 3–21.
  5. Adachi, T.; Nakamura, Y. Aptamers: A review of their chemical properties and modifications for therapeutic application. Molecules 2019, 24, 4229.
  6. Odeh, F.; Nsairat, H.; Alshaer, W.; Ismail, M.A.; Esawi, E.; Qaqish, B.; Al Bawab, A.; Ismail, S.I. Aptamers chemistry: Chemical modifications and conjugation strategies. Molecules 2020, 25, 3.
  7. Parashar, A. Aptamers in therapeutics. J. Clin. Diagn. Res. 2016, 10, BE01–BE06.
  8. Maier, K.E.; Levy, M. From selection hits to clinical leads: Progress in aptamer discovery. Mol. Ther. Methods Clin. Dev. 2016, 5, 16014–16023.
  9. Nimjee, S.M.; White, R.R.; Becker, R.C.; Sullenger, B.A. Aptamers as therapeutics. Annu. Rev. Pharmacol. Toxicol. 2017, 57, 61–79.
  10. Zhou, J.; Rossi, J. Aptamers as targeted therapeutics: Current potential and challenges. Nat. Rev. Drug Discov. 2017, 16, 181–202.
  11. Ismail, S.I.; Alshaer, W. Therapeutic aptamers in discovery, preclinical and clinical stages. Adv. Drug Deliv. Rev. 2018, 134, 51–64.
  12. Morita, Y.; Leslie, M.; Kameyama, H.; Volk, D.E.; Tanaka, T. Aptamer therapeutics in cancer: Current and future. Cancers 2018, 10, 80.
  13. Ali, M.H.; Elsherbiny, M.E.; Emara, M. Updates on aptamer research. Int. J. Mol. Sci. 2019, 20, 2511.
  14. Zhang, Y.; Lai, B.S.; Juhas, M. Recent advances in aptamer discovery and applications. Molecules 2019, 24, 941.
  15. Wang, T.; Chen, C.; Larcher, L.M.; Barrero, R.A.; Veedu, R.N. Three decades of nucleic acid aptamer technologies: Lessons learned, progress and opportunities on aptamer development. Biotechnol. Adv. 2019, 37, 28–50.
  16. Santosh, B.; Yadava, P.K. Nucleic acid aptamers: Research tools in disease diagnostics and therapeutics. Biomed. Res. Int. 2014, 2014, 50451–50464.
  17. Ma, H.; Liu, J.; Ali, M.M.; Mahmood, M.A.I.; Labanieh, L.; Lu, M.; Iqbal, S.M.; Zhang, Q.; Zhao, W.; Wan, Y. Nucleic acid aptamers in cancer research, diagnosis and therapy. Chem. Soc. Rev. 2015, 44, 1240–1256.
  18. Ku, T.H.; Zhang, T.; Luo, H.; Yen, T.M.; Chen, P.W.; Han, Y.; Lo, Y.H. Nucleic acid aptamers: An emerging tool for biotechnology and biomedical sensing. Sensors 2015, 15, 16281–16313.
  19. Chandola, C.; Kalme, S.; Casteleijn, M.G.; Urtti, A.; Neerathilingam, M. Application of aptamers in diagnostics, drug-delivery and imaging. J. Biosci. 2016, 41, 535–561.
  20. Musumeci, D.; Platella, C.; Riccardi, C.; Moccia, F.; Montesarchio, D. Fluorescence sensing using DNA aptamers in cancer research and clinical diagnostics. Cancers 2017, 9, 174.
  21. Dhiman, A.; Kalra, P.; Bansal, V.; Bruno, J.G.; Sharma, T.K. Aptamer-based point-of-care diagnostic platforms. Sens. Actuators B Chem. 2017, 246, 535–553.
  22. Hori, S.I.; Herrera, A.; Rossi, J.J.; Zhou, J. Current advances in aptamers for cancer diagnosis and therapy. Cancers 2018, 10, 9.
  23. Kulabhusan, P.K.; Hussain, B.; Yüce, M. Current perspectives on aptamers as diagnostic tools and therapeutic agents. Pharmaceutics 2020, 12, 646.
  24. Tuerk, C.; Gold, L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 1990, 249, 505–510.
  25. Ellington, A.D.; Szostak, J.W. Selection in vitro of single-stranded DNA molecules that fold into specific ligand-binding structures. Nature 1992, 355, 850–852.
  26. Stoltenburg, R.; Reinemann, C.; Strehlitz, B. SELEX-A (r)evolutionary method to generate high-affinity nucleic acid ligands. Biomol. Eng. 2007, 24, 381–403.
  27. Keefe, A.D.; Cload, S.T. SELEX with modified nucleotides. Curr. Opin. Chem. Biol. 2008, 12, 448–456.
  28. Darmostuk, M.; Rimpelova, S.; Gbelcova, H.; Ruml, T. Current approaches in SELEX: An update to aptamer selection technology. Biotechnol. Adv. 2014, 33, 1141–1161.
  29. Wu, Y.X.; Kwon, Y.J. Aptamers: The “evolution” of SELEX. Methods 2016, 106, 21–28.
  30. Antipova, O.M.; Zavyalova, E.G.; Golovin, A.V.; Pavlova, G.V.; Kopylov, A.M.; Reshetnikov, R.V. Advances in the application of modified nucleotides in SELEX technology. Biochemistry 2018, 83, 1161–1172.
  31. Bayat, P.; Nosrati, R.; Alibolandi, M.; Rafatpanah, H.; Abnous, K.; Khedri, M.; Ramezani, M. SELEX methods on the road to protein targeting with nucleic acid aptamers. Biochimie 2018, 154, 132–155.
  32. Sola, M.; Menon, A.; Moreno, B.; Meraviglia-Crivelli, D.; Soldevilla, M.; Cartón-García, F.; Pastor, F. Aptamers against live targets: Is in vivo SELEX finally coming to edge? Mol. Ther. Nucleic Acids 2020, 21, 192–204.
  33. Vandghanooni, S.; Eskandani, M.; Barar, J.; Omidi, Y. Recent advances in aptamer-armed multimodal theranostic nanosystems for imaging and targeted therapy of cancer. Eur. J. Pharm. Sci. 2018, 117, 301–312.
  34. He, F.; Wen, N.; Xiao, D.; Yan, J.; Xiong, H.; Cai, S.; Liu, Z.; Liu, Y. Aptamer-based targeted drug delivery systems: Current potential and challenges. Curr. Med. Chem. 2020, 27, 2189–2219.
  35. Broude, N.E. Stem-loop oligonucleotides: A robust tool for molecular biology and biotechnology. Trends Biotechnol. 2002, 20, 249–256.
  36. Musumeci, D.; Riccardi, C.; Montesarchio, D. G-quadruplex forming oligonucleotides as anti-HIV agents. Molecules 2015, 20, 17511–17532.
  37. Neidle, S. Quadruplex nucleic acids as novel therapeutic targets. J. Med. Chem. 2016, 59, 5987–6011.
  38. Platella, C.; Riccardi, C.; Montesarchio, D.; Roviello, G.N.; Musumeci, D. G-quadruplex-based aptamers against protein targets in therapy and diagnostics. Biochim. Biophys. Acta Gen. Subj. 2017, 1861, 1429–1447.
  39. Kwok, C.K.; Merrick, C.J. G-Quadruplexes: Prediction, characterization, and biological application. Trends Biotechnol. 2017, 35, 997–1013.
  40. Roxo, C.; Kotkowiak, W.; Pasternak, A. G-quadruplex forming aptamers characteristics, applications, and perspectives. Molecules 2019, 24, 3781.
  41. Gatto, B.; Palumbo, M.; Sissi, C. Nucleic acid aptamers based on the G-quadruplex structure: Therapeutic and diagnostic potential. Curr. Med. Chem. 2009, 16, 1248–1265.
  42. Collie, G.W.; Parkinson, G.N. The application of DNA and RNA G-quadruplexes to therapeutic medicines. Chem. Soc. Rev. 2011, 40, 5867–5892.
  43. Dolinnaya, N.G.; Ogloblina, A.M.; Yakubovskaya, M.G. Structure, properties, and biological relevance of the DNA and RNA G-quadruplexes: Overview 50 years after their discovery. Biochemistry 2016, 81, 1602–1649.
  44. Tucker, W.O.; Shum, K.T.; Tanner, J.A. G-quadruplex DNA aptamers and their ligands: Structure, function and application. Curr. Pharm. Des. 2012, 18, 2014–2026.
  45. Bhattacharyya, D.; Arachchilage, G.M.; Basu, S. Metal cations in G-quadruplex folding and stability. Front. Chem. 2016, 4, 38.
  46. Largy, E.; Marchand, A.; Amrane, S.; Gabelica, V.; Mergny, J.L. Quadruplex turncoats: Cation-dependent folding and stability of quadruplex-DNA double switches. J. Am. Chem. Soc. 2016, 138, 2780–2792.
  47. Largy, E.; Mergny, J.L.; Gabelica, V. Role of alkali metal ions in G-quadruplex nucleic acid structure and stability. Met. Ions Life Sci. 2016, 16, 203–258.
  48. Musumeci, D.; Montesarchio, D. Polyvalent nucleic acid aptamers and modulation of their activity: A focus on the thrombin binding aptamer. Pharmacol. Ther. 2012, 136, 202–215.
  49. Vorobyeva, M.; Vorobjev, P.; Venyaminova, A. Multivalent aptamers: Versatile tools for diagnostic and therapeutic applications. Molecules 2016, 21, 1613.
  50. Gao, S.; Zheng, X.; Jiao, B.; Wang, L. Post-SELEX optimization of aptamers. Anal. Bioanal. Chem. 2016, 408, 4567–4573.
  51. Hasegawa, H.; Savory, N.; Abe, K.; Ikebukuro, K. Methods for improving aptamer binding affinity. Molecules 2016, 21, 421.
  52. Huntington, J.A. Molecular recognition mechanisms of thrombin. J. Thromb. Haemost. 2005, 3, 1861–1872.
  53. Wolberg, A.S. Thrombin generation and fibrin clot structure. Blood Rev. 2007, 21, 131–142.
  54. Di Cera, E. Thrombin. Mol. Aspects Med. 2008, 29, 203–254.
  55. Licari, L.G.; Kovacic, J.P. Thrombin physiology and pathophysiology. J. Vet. Emerg. Crit. Care 2009, 19, 11–22.
  56. Mazepa, M.; Hoffman, M.; Monroe, D. Superactivated platelets: Thrombus regulators, thrombin generators, and potential clinical targets. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 1747–1752.
  57. Posma, J.J.N.; Posthuma, J.J.; Spronk, H.M.H. Coagulation and non-coagulation effects of thrombin. J. Thromb. Haemost. 2016, 14, 1908–1916.
  58. Huntington, J.A.; Baglin, T.P. Targeting thrombin rational drug design from natural mechanisms. Trends Pharmacol. Sci. 2003, 24, 589–595.
  59. Hirsh, J. Current anticoagulant therapy unmet clinical needs. Thromb. Res. 2003, 109, S1–S8.
  60. Gómez Outes, A.; Suárez Gea, M.L.; Pozo Hernández, C.; Lecumberri, R.; Rocha, E.; Vargas Castrillón, E. New parenteral anticoagulants in development. Ther. Adv. Cardiovasc. Dis. 2011, 5, 33–59.
  61. Zavyalova, E.G.; Ustinov, N.; Golovin, A.; Pavlova, G.; Kopylov, A. G-quadruplex aptamers to human thrombin versus other direct thrombin inhibitors: The focus on mechanism of action and drug efficiency as anticoagulants. Curr. Med. Chem. 2016, 23, 2230–2244.
  62. Becker, R.C.; Povsic, T.; Cohen, M.G.; Rusconi, C.P.; Sullenger, B. Nucleic acid aptamers as antithrombotic agents: Opportunities in extracellular therapeutics. Thromb. Haemost. 2010, 103, 586–595.
  63. Nimjee, S.M.; Povsic, T.J.; Sullenger, B.A.; Becker, R.C. Translation and clinical development of antithrombotic aptamers. Nucleic Acid Ther. 2016, 26, 147–155.
  64. Ponce, A.T.; Hong, K.L. A mini-review: Clinical development and potential of aptamers for thrombotic events treatment and monitoring. Biomedicines 2019, 7, 55.
  65. Riccardi, C.; Napolitano, E.; Platella, C.; Musumeci, D.; Montesarchio, D. G-quadruplex-based aptamers targeting human thrombin: Discovery, chemical modifications and antithrombotic effects. Pharmacol. Ther. 2020, 107649.
  66. Tasset, D.M.; Kubik, M.F.; Steiner, W. Oligonucleotide inhibitors of human thrombin that bind distinct epitopes. J. Mol. Biol. 1997, 272, 688–698.
  67. Marson, G.; Palumbo, M.; Sissi, C. Folding versus charge: Understanding selective target recognition by the thrombin aptamers. Curr. Pharm. Des. 2012, 18, 2027–2035.
  68. Bock, L.C.; Griffin, L.C.; Latham, J.A.; Vermaas, E.H.; Toole, J.J. Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature 1992, 355, 564–566.
  69. Macaya, R.F.; Schultze, P.; Smith, F.W.; Roe, J.A.; Feigon, J. Thrombin-binding DNA aptamer forms a unimolecular quadruplex structure in solution. Proc. Natl. Acad. Sci. USA 1993, 90, 3745–3749.
  70. Wang, K.Y.; Bolton, P.H.; McCurdy, S.; Shea, R.G.; Swaminathan, S. A DNA aptamer which binds to and inhibits thrombin exhibits a new structural motif for DNA. Biochemistry 1993, 32, 1899–1904.
  71. Wang, K.Y.; Bolton, P.H.; Krawczyk, S.H.; Bischofberger, N.; Swaminathan, S. The tertiary structure of a DNA aptamer which binds to and inhibits thrombin determines activity. Biochemistry 1993, 32, 11285–11292.
  72. Padmanabhan, K.; Padmanabhan, K.P.; Ferrara, J.D.; Sadler, J.E.; Tulinsky, A. The structure of α-thrombin inhibited by a 15-mer single-stranded DNA aptamer. J. Biol. Chem. 1993, 268, 17651–17654.
  73. Schultze, P.; Macaya, R.F.; Feigon, J. Three-dimensional solution structure of the thrombin-binding DNA aptamer d(GGTTGGTGTGGTTGG). J. Mol. Biol. 1994, 235, 1532–1547.
  74. Padmanabhan, K.; Tulinsky, A. An ambiguous structure of a DNA 15-mer thrombin complex. Acta Crystallogr. Sect. D Biol. Crystallogr. 1996, 52, 272–282.
  75. Kelly, J.A.; Feigon, J.; Yeates, T.O. Reconciliation of the X-ray and NMR structures of the thrombin-binding aptamer d(GGTTGGTGTGGTTGG). J. Mol. Biol. 1996, 256, 417–422.
  76. Zavyalova, E.G.; Golovin, A.; Reshetnikov, R.; Mudrik, N.; Panteleyev, D.; Pavlova, G.; Kopylov, A. Novel modular DNA aptamer for human thrombin with high anticoagulant activity. Curr. Med. Chem. 2011, 18, 3343–3350.
  77. Poniková, S.; Tlučková, K.; Antalík, M.; Víglaský, V.; Hianik, T. The circular dichroism and differential scanning calorimetry study of the properties of DNA aptamer dimers. Biophys. Chem. 2011, 155, 29–35.
  78. Amato, T.; Virgilio, A.; Pirone, L.; Vellecco, V.; Bucci, M.; Pedone, E.; Esposito, V.; Galeone, A. Investigating the properties of TBA variants with twin thrombin binding domains. Sci. Rep. 2019, 9, 9184.
  79. Müller, J.; Wulffen, B.; Pötzsch, B.; Mayer, G. Multidomain targeting generates a high-affinity thrombin-inhibiting bivalent aptamer. ChemBioChem 2007, 8, 2223–2226.
  80. Müller, J.; Freitag, D.; Mayer, G.; Pötzsch, B. Anticoagulant characteristics of HD1-22, a bivalent aptamer that specifically inhibits thrombin and prothrombinase. J. Thromb. Haemost. 2008, 6, 2105–2112.
  81. Hasegawa, H.; Taira, K.I.; Sode, K.; Ikebukuro, K. Improvement of aptamer affinity by dimerization. Sensors 2008, 8, 1090–1098.
  82. Tian, L.; Heyduk, T. Bivalent ligands with long nanometer-scale flexible linkers. Biochemistry 2009, 48, 264–275.
  83. Hughes, Q.W.; Le, B.T.; Gilmore, G.; Baker, R.I.; Veedu, R.N. Construction of a bivalent thrombin binding aptamer and its antidote with improved properties. Molecules 2017, 22, 1770.
  84. Ahmad, K.M.; Xiao, Y.; Soh, H.T. Selection is more intelligent than design: Improving the affinity of a bivalent ligand through directed evolution. Nucleic Acids Res. 2012, 40, 11777–11783.
  85. Kim, Y.; Cao, Z.; Tan, W. Molecular assembly for high-performance bivalent nucleic acid inhibitor. Proc. Natl. Acad. Sci. USA 2008, 105, 5664–5669.
  86. Di Giusto, D.A.; King, G.C. Construction, stability, and activity of multivalent circular anticoagulant aptamers. J. Biol. Chem. 2004, 279, 46483–46489.
  87. Di Giusto, D.A.; Knox, S.M.; Lai, Y.; Tyrelle, G.D.; Aung, M.T.; King, G.C. Multitasking by multivalent circular DNA aptamers. ChemBioChem 2006, 7, 535–544.
  88. Hsiao, K.Y.; Sun, H.S.; Tsai, S.J. Circular RNA—New member of noncoding RNA with novel functions. Exp. Biol. Med. 2017, 242, 1136–1141.
  89. Li, J.; Mohammed-Elsabagh, M.; Paczkowski, F.; Li, Y. Circular nucleic acids: Discovery, functions and applications. ChemBioChem 2020, 22, 1547–1566.
  90. Riccardi, C.; Meyer, A.; Vasseur, J.J.; Russo Krauss, I.; Paduano, L.; Oliva, R.; Petraccone, L.; Morvan, F.; Montesarchio, D. Stability is not everything: The case of the cyclization of the thrombin binding aptamer. ChemBioChem 2019, 20, 1789–1794.
  91. Riccardi, C.; Meyer, A.; Vasseur, J.J.; Russo Krauss, I.; Paduano, L.; Morvan, F.; Montesarchio, D. Fine-tuning the properties of the thrombin binding aptamer through cyclization: Effect of the 5′-3′ connecting linker on the aptamer stability and anticoagulant activity. Bioorg. Chem. 2020, 94, 103379.
  92. Riccardi, C.; Meyer, A.; Vasseur, J.J.; Cavasso, D.; Russo Krauss, I.; Paduano, L.; Morvan, F.; Montesarchio, D. Design, synthesis and characterization of cyclic NU172 analogues: A biophysical and biological insight. Int. J. Mol. Sci. 2020, 21, 3860.
  93. Hicke, B.J.; Watson, S.R.; Koenig, A.; Lynott, C.K.; Bargatze, R.F.; Chang, Y.F.; Ringquist, S.; Moon-McDermott, L.; Jennings, S.; Fitzwater, T.; et al. DNA aptamers block L-selectin function in vivo: Inhibition of human lymphocyte trafficking in SCID mice. J. Clin. Investig. 1996, 98, 2688–2692.
  94. Russo Krauss, I.; Merlino, A.; Giancola, C.; Randazzo, A.; Mazzarella, L.; Sica, F. Thrombin-aptamer recognition: A revealed ambiguity. Nucleic Acids Res. 2011, 39, 7858–7867.
  95. Russo Krauss, I.; Merlino, A.; Randazzo, A.; Novellino, E.; Mazzarella, L.; Sica, F. High-resolution structures of two complexes between thrombin and thrombin-binding aptamer shed light on the role of cations in the aptamer inhibitory activity. Nucleic Acids Res. 2012, 40, 8119–8128.
  96. Yigit, M.V.; Mazumdar, D.; Lu, Y. MRI detection of thrombin with aptamer functionalized superparamagnetic iron oxide nanoparticles. Bioconjugate Chem. 2008, 19, 412–417.
  97. Musumeci, D.; Oliviero, G.; Roviello, G.N.; Bucci, E.M.; Piccialli, G. G-quadruplex-forming oligonucleotide conjugated to magnetic nanoparticles: Synthesis, characterization, and enzymatic stability assays. Bioconjugate Chem. 2012, 23, 382–391.
  98. Yu, J.; Yang, L.; Liang, X.; Dong, T.; Liu, H. Bare magnetic nanoparticles as fluorescence quenchers for detection of thrombin. Analyst 2015, 140, 4114–4120.
  99. Shiang, Y.C.; Huang, C.C.; Wang, T.H.; Chien, C.W.; Chang, H.T. Aptamer-conjugated nanoparticles efficiently control the activity of thrombin. Adv. Funct. Mater. 2010, 20, 3175–3182.
  100. Shiang, Y.C.; Hsu, C.L.; Huang, C.C.; Chang, H.T. Gold nanoparticles presenting hybridized self-assembled aptamers that exhibit enhanced inhibition of thrombin. Angew. Chem. Int. Ed. Eng. 2011, 50, 7660–7665.
  101. Hsu, C.L.; Chang, H.T.; Chen, C.T.; Wei, S.C.; Shiang, Y.C.; Huang, C.C. Highly efficient control of thrombin activity by multivalent nanoparticles. Chem. A Eur. J. 2011, 17, 10994–11000.
  102. Hsu, C.L.; Wei, S.C.; Jian, J.W.; Chang, H.T.; Chen, W.H.; Huang, C.C. Highly flexible and stable aptamer-caged nanoparticles for control of thrombin activity. RSC Adv. 2012, 2, 1577–1584.
  103. Huang, S.S.; Wei, S.C.; Chang, H.T.; Lin, H.J.; Huang, C.C. Gold nanoparticles modified with self-assembled hybrid monolayer of triblock aptamers as a photoreversible anticoagulant. J. Control. Release 2016, 221, 9–17.
  104. Gao, L.; Cui, Y.; He, Q.; Yang, Y.; Fei, J.; Li, J. Selective recognition of co-assembled thrombin aptamer and docetaxel on mesoporous silica nanoparticles against tumor cell proliferation. Chemistry 2011, 17, 13170–13174.
  105. Babu, E.; Mareeswaran, P.M.; Rajagopal, S. Highly sensitive optical biosensor for thrombin based on structure switching aptamer-luminescent silica nanoparticles. J. Fluoresc. 2013, 23, 137–146.
  106. Yue, Q.; Shen, T.; Wang, L.; Xu, S.; Li, H.; Xue, Q.; Zhang, Y.; Gu, X.; Zhang, S.; Liu, J. A convenient sandwich assay of thrombin in biological media using nanoparticle-enhanced fluorescence polarization. Biosens. Bioelectron. 2014, 56, 231–236.
  107. Riccardi, C.; Russo Krauss, I.; Musumeci, D.; Morvan, F.; Meyer, A.; Vasseur, J.J.; Paduano, L.; Montesarchio, D. Fluorescent thrombin binding aptamer-tagged nanoparticles for an efficient and reversible control of thrombin activity. ACS Appl. Mater. Interfaces 2017, 9, 35574–35587.
  108. Lai, P.X.; Mao, J.Y.; Unnikrishnan, B.; Chu, H.W.; Wu, C.W.; Chang, H.T.; Huang, C.C. Self-assembled, bivalent aptamers on graphene oxide as an efficient anticoagulant. Biomater. Sci. 2018, 6, 1882–1891.
  109. Lin, T.-X.; Lai, P.-X.; Mao, J.-Y.; Chu, H.-W.; Unnikrishnan, B.; Anand, A.; Huang, C.-C. Supramolecular aptamers on graphene oxide for efficient inhibition of thrombin activity. Front. Chem. 2019, 7.
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Subjects: Chemistry, Medicinal
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Claudia Riccardi
,
Ettore Napolitano
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Domenica Musumeci
,
Daniela Montesarchio
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Revisions: 3 times (View History)
Update Date: 01 Dec 2020
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