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Smart Designed Aptamers: Applications & Effective Design Options


The term aptamer is derived from the Latin 'aptus' meaning "to fit" and is based on the strong binding of single stranded oligos to specific targets based on structural conformation. Aptamers are single-stranded RNA or DNA oligonucleotides 15 to 60 base in length that bind with high affinity to specific molecular targets; most aptamers to proteins bind with Kds (equilibrium constant) in the range of 1 pM to 1 nM similar to monoclonal antibodies. These nucleic acid ligands bind to nucleic acid, proteins, small organic compounds, and even entire organisms. Aptamers have many potential uses in intracellular processes studies, medicine and technology (1-7, excellent background and review articles).

In addition to the genetic information encoded by nucleic acids they also function as highly specific affinity ligands by molecular interaction based on the three dimensional folding pattern. The three dimensional complex shape of a single stranded oligonucleotide is primarily due to the base composition led intra-molecular hybridization that initiates folding to a particular molecular shape. This molecular shape assists in binding through shape specific recognition to it targets leading to considerable three dimensional structure stability and thus the high degree of affinity. Natural examples of molecular shape recognition interactions of nucleic acids with proteins are tRNA, ribozymes, DNA binding proteins and DNAzymes (8,9).

Theoretically it is possible to select aptamers virtually against any molecular target; aptamers have been selected for small molecules, peptides, proteins as well as viruses and bacteria. The aptamers are selected by incubating the target molecule in a large pool of oligonucleotide (usually 40 to 60mers), the pool size of the oligonucleotide is from 1010 to 1020. The large pool size of the oligonucleotide ensures the selection and isolation of the specific aptamer. The structural and informational complexity of the oligonucleotide pool and its functional activity is an interesting and active area to develop an algorithm based development of nucleic acid ligands (10). Aptamers can distinguish between closely related but non-identical members of a protein family, or between different functional or conformational states of the same protein. In a striking example of specificity, an aptamer to the small molecule theophylline (1,3-dimethylxanthine) binds with 10,000-fold lower affinity to caffeine (1,3,7-trimethylxanthine) that differs from theophylline by a single methyl group. The protocol called systematic evolution of ligands by exponential enrichment (SELEX) is generally used with modification and variations for the selection of specific aptamers. Using this process, it is possible to develop new aptamers in as little as two weeks (1-4).

Gene Link routinely synthesizes the random oligonucleotide pools that are used for the initial specific aptamer selection procedure for SELEX. A version of the SELEX protocol is given below.

Smart Aptamers

The structural stability of Aptamers as affinity ligands can be calculated by strict criteria of equilibrium (Kd), kinetic (koff, kon) and thermodynamic (?H, ?S) parameters of bio-molecular interaction. Thus "Smart Aptamers" term was coined for a pool of aptamers with different equilibrium constants (Kd) such that they will be effective in varying concentration range of the target. Kinetic capillary electrophoresis (KCE) has been recently proven to generate smart DNA aptamers with a wide range of predefined values of Kd and high selectivity (11).


1. Ellington, A.D., and J.W. Szostak. J.W (1990), In vitro selection of RNA molecules that bind specific ligands. Nature 346: 818-822.
2. Tuerk, C. and L. Gold, L. (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505-510.
3. Wilson, D.S., Szostak, J.W. (1999). In vitro selection of functional nucleic acids. Annu Rev Biochem 68, 611-647.
4. The Aptamer Handbook. Edited by S. Klussmann. (2006) WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
5. S. Tombelli, S., Minunni, M. and M. Mascini. (2005) Analytical applications of aptamers. Biosensors and Bioelectronics 20: 2424-2434.
6. Lee, J.F., Stovall, G.M. and Ellington, A.D. (2006) Aptamer therapeutics advance. Current Opinion in Chemical Biology 10:282-289.
7. Shahid M. Nimjee, Christopher P. Rusconi and Bruce A. Sullenger, B.A (2005) Apaterms: An emerging class of therapeutics. Annu. Rev. Med. 56:555-83. Antidote control of aptamer activity enables safe, tightly controlled therapeutics. Aptamers may prove useful in the treatment of a wide variety of human maladies, including infectious diseases, cancer, and cardiovascular disease.
8. Razvan, N., Shirley Mei, S., Zhongjie Liu, Z. and Yingfu Li. Y. (2004) Engineering DNA aptamers and DNA enzymes with fluorescence-signaling properties. Pure Appl. Chem.,76:1547-1561.
9. Breaker, R.R. DNA Enzymes. (1997) Nat Biotechnology. 15(5):427-31.
10. Carothers, J.M., Oestreich, S.C., Davis,J.H. and Jack W. Szostak, J.W. (2004)
Informational Complexity and Functional Activity of RNA Structures. J. Am Chem. Soc. 126:5130-5137.
11. Drabovich, A.P., Okhonin, V., Berezovski, M. and Krylov, S.N. (2007) Smart aptamers facilitate multi-probe affinity analysis of proteins with ultra-wide dynamic range of measured concentrations. J. Am. Chem. Soc.129: 7260-7261.

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