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Structure of an RNA aptamer specific for biotin. The aptamer surface and backbone are shown in yellow. Biotin (spheres) fits snugly into a cavity of the RNA surface

Aptamers (from the Latin aptus – fit, and Greek meros – part) are oligonucleotide or peptide molecules that bind to a specific target molecule. Aptamers are usually created by selecting them from a large random sequence pool, but natural aptamers also exist in riboswitches. Aptamers can be used for both basic research and clinical purposes as macromolecular drugs. Aptamers can be combined with ribozymes to self-cleave in the presence of their target molecule. These compound molecules have additional research, industrial and clinical applications.

More specifically, aptamers can be classified as

  • DNA or RNA or XNA aptamers. They consist of (usually short) strands of oligonucleotides.
  • Peptide aptamers. They consist of one (or more) short variable peptide domains, attached at both ends to a protein scaffold.


Nucleic acid[edit]

Nucleic acid aptamers are nucleic acid species (next-gen antibody mimics) that exhibit affinity for a given target with selectivity and specificity comparable to antibodies. Nucleic acid aptamers can consist of either RNA or DNA. Nucleic acid aptamers are generated via in-vitro selection methods such as SELEX (systematic evolution of ligands by exponential enrichment) to express affinity for targets ranging from small ligands such as heavy metal ions and small molecules, up to larger lignads such as proteins and cells.[1] At the molecular level, the aptamer-ligand interaction is mediated through non-covalent forces; electrostatic interactions, hydrophobic interactions, pi-pi orbital stacking, and hydrogen bonding interactions. The molecular recognition properties of aptamers present growing use in biotechnological and therapeutic applications. Aptamers offer advantages over antibodies as they can be engineered completely in vitro, are readily produced by chemical synthesis, possess desirable storage properties, and elicit little or no immunogenicity in therapeutic applications.[2]

In 1990, two labs independently developed the technique of selection: the Gold lab, using the term SELEX for their process of selecting RNA ligands against T4 DNA polymerase; and the Szostak lab, coining the term in vitro selection, selecting RNA ligands against various organic dyes. The Szostak lab also coined the term aptamer (from the Latin, apto, meaning 'to fit') for these nucleic acid-based ligands. Two years later, the Szostak lab and Gilead Sciences, independent of one another, used in vitro selection schemes to evolve single stranded DNA ligands for organic dyes and human coagulant, thrombin (see anti-thrombin aptamers), respectively. There does not appear to be any systematic differences between RNA and DNA aptamers, save the greater intrinsic chemical stability of DNA.

The notion of selection in vitro was preceded twenty-plus years prior when Sol Spiegelman used a Qbeta replication system as a way to evolve a self-replicating molecule.[3] In addition, a year before the publishing of in vitro selection and SELEX, Gerald Joyce used a system that he termed 'directed evolution' to alter the cleavage activity of a ribozyme.

Since the discovery of aptamers, many researchers have used aptamer selection as a means for application and discovery. In 2001, the process of in vitro selection was automated[4][5][6] by J. Colin Cox in the Ellington lab at the University of Texas at Austin, reducing the duration of a selection experiment from six weeks to three days.

While the process of artificial engineering of nucleic acid ligands is highly interesting to biology and biotechnology, the notion of aptamers in the natural world had yet to be uncovered until 2002 when two groups led by Ronald Breaker and Evgeny Nudler discovered a nucleic acid-based genetic regulatory element (which was named riboswitch) that possesses similar molecular recognition properties to the artificially made aptamers. In addition to the discovery of a new mode of genetic regulation, this adds further credence to the notion of an 'RNA World', a postulated stage in time in the origins of life on Earth.

Both DNA and RNA aptamers show robust binding affinities for various targets.[7][8][9][10] DNA and RNA aptamers have been selected for the same target. These targets include lysozyme,[11] thrombin,[12] human immunodeficiency virus trans-acting responsive element (HIV TAR),[13] hemin,[14] interferon γ,[15] vascular endothelial growth factor (VEGF),[16] prostate specific antigen (PSA),[17][18] dopamine,[19] and the non-classical oncogene, heat shock factor 1 (HSF1).[20] In the case of lysozyme, HIV TAR, VEGF and dopamine the DNA aptamer is the analog of the RNA aptamer, with thymine replacing uracil. The hemin, thrombin, and interferon γ, DNA and RNA aptamers were selected through independent selections and have unique sequences. Considering that not all DNA analogs of RNA aptamers show functionality, the correlation between DNA and RNA sequence and their structure and function requires further investigation.

Lately, a concept of smart aptamers, and smart ligands in general, has been introduced. It describes aptamers that are selected with pre-defined equilibrium (), rate (, ) constants and thermodynamic (ΔH, ΔS) parameters of aptamer-target interaction. Kinetic capillary electrophoresis is the technology used for the selection of smart aptamers. It obtains aptamers in a few rounds of selection.

Recent developments in aptamer-based therapeutics have been rewarded in the form of the first aptamer-based drug approved by the U.S. Food and Drug Administration (FDA) in treatment for age-related macular degeneration (AMD), called Macugen offered by OSI Pharmaceuticals. In addition, the company NeoVentures Biotechnology Inc.[21] has successfully commercialized the first aptamer based diagnostic platform for analysis of mycotoxins in grain. Many contract companies develop aptamers and aptabodies to replace antibodies in research, diagnostic platforms, drug discovery, and therapeutics.

Non-modified aptamers are cleared rapidly from the bloodstream, with a half-life of minutes to hours, mainly due to nuclease degradation and clearance from the body by the kidneys, a result of the aptamer's inherently low molecular weight. Unmodified aptamer applications currently focus on treating transient conditions such as blood clotting, or treating organs such as the eye where local delivery is possible. This rapid clearance can be an advantage in applications such as in vivo diagnostic imaging. An example is a tenascin-binding aptamer under development by Schering AG for cancer imaging. Several modifications, such as 2'-fluorine-substituted pyrimidines, polyethylene glycol (PEG) linkage, etc. (both of which are used in Macugen, an FDA-approved aptamer) are available to scientists with which to increase the serum half-life of aptamers easily to the day or even week time scale.

Another approach to increase the nuclease resistance of aptamers is to develop Spiegelmers, which are composed entirely of an unnatural L-ribonucleic acid backbone. A Spiegelmer of the same sequence has the same binding properties of the corresponding RNA aptamer, except it binds to the mirror image of its target molecule.

In addition to the development of aptamer-based therapeutics, many researchers such as the Ellington lab have been developing diagnostic techniques for aptamer based plasma protein profiling called aptamer plasma proteomics. This technology will enable future multi-biomarker protein measurements that can aid diagnostic distinction of disease versus healthy states.

Furthermore, the Hirao lab applied a genetic alphabet expansion using an unnatural base pair[22][23] to SELEX and achieved the generation of high affinity DNA aptamers.[24] Only a few hydrophobic interactions from an unnatural fifth base significantly augments the aptamer affinity to target proteins.

As a resource for all in vitro selection and SELEX experiments, the Ellington lab has developed the Aptamer Database cataloging all published experiments.

Optimer ligands[edit]

Optimer ligands are next-generation aptamers.[25] Based on aptamer technology, Optimer ligands are selected through iterative rounds of in vitro selection to identify ligands that bind with high specificity, low cross-reactivity and specific binding kinetics.[26][27][28] Following discovery they are further engineered to offer increased stability,[29] smaller size and improved manufacturability.[30] The improved manufacturing profile of Optimer ligands increases scalability, lot-to-lot consistency and reduces cost compared to standard aptamers.[31]

Optimer ligands are being applied across therapeutics,[32][33] drug delivery,[34][35][36] bioprocessing,[37][38] diagnostics,[39][40][41][42][43][26][28] and basic research.[26]

Split aptamers[edit]

Split aptamers are composed of two or more DNA strands that mimic segments of a larger parent aptamer. The ability of each component strand to bind targets will depend on the location of the nick and the secondary structures of the daughter strands, with the most prominent structures being three-way junctions.[44] The presence of a target molecule can promote assembly of the DNA fragments.[45] Once assembled, the strands can be chemically or enzymatically ligated into a single strand. Analytes for which split aptamers have been developed include the protein α-thrombin, ATP, and cocaine. Split aptamers are a potential template for biosensors in analogy to split protein systems.


Peptide aptamers [46] are artificial proteins selected or engineered to bind specific target molecules. These proteins consist of one or more peptide loops of variable sequence displayed by a protein scaffold. They are typically isolated from combinatorial libraries and often subsequently improved by directed mutation or rounds of variable region mutagenesis and selection. In vivo, peptide aptamers can bind cellular protein targets and exert biological effects, including interference with the normal protein interactions of their targeted molecules with other proteins. Libraries of peptide aptamers have been used as "mutagens", in studies in which an investigator introduces a library that expresses different peptide aptamers into a cell population, selects for a desired phenotype, and identifies those aptamers that cause the phenotype. The investigator then uses those aptamers as baits, for example in yeast two-hybrid screens to identify the cellular proteins targeted by those aptamers. Such experiments identify particular proteins bound by the aptamers, and protein interactions that the aptamers disrupt, to cause the phenotype.[47][48] In addition, peptide aptamers derivatized with appropriate functional moieties can cause specific postranslational modification of their target proteins, or change the subcellular localization of the targets.[49]

Peptide aptamers can also recognize targets in vitro. They have found use in lieu of antibodies in biosensors [50][51] and used to detect active isoforms of proteins from populations containing both inactive and active protein forms.[52] Derivatives known as tadpoles, in which peptide aptamer "heads" are covalently linked to unique sequence double-stranded DNA "tails", allow quantification of scarce target molecules in mixtures by PCR (using, for example, the quantitative real-time polymerase chain reaction) of their DNA tails.[53]

The peptides that form the aptamer variable regions are synthesized as part of the same polypeptide chain as the scaffold and are constrained at their N and C termini by linkage to it. This double structural constraint decreases the diversity of the conformations that the variable regions can adopt,[54] and this reduction in conformational diversity lowers the entropic cost of molecular binding when interaction with the target causes the variable regions to adopt a single conformation. As a consequence, peptide aptamers can bind their targets tightly, with binding affinities comparable to those shown by antibodies (nanomolar range).

Peptide aptamer scaffolds are typically small, ordered, soluble proteins. The first scaffold,[46] which is still widely used,[55] is Escherichia coli thioredoxin, the trxA gene product (TrxA). In these molecules, a single peptide of variable sequence is displayed instead of the Gly-Pro motif in the TrxA -Cys-Gly-Pro-Cys- active site loop. Improvements to TrxA include substitution of serines for the flanking cysteines, which prevents possible formation of a disulfide bond at the base of the loop, introduction of a D26A substitution to reduce oligomerization, and optimization of codons for expression in human cells,.[55][56] Reviews in 2015 have reported studies using 12 [55] and 20 [57] other scaffolds.

Peptide aptamer selection can be made using different systems, but the most used is currently the yeast two-hybrid system. Peptide aptamers can also be selected from combinatorial peptide libraries constructed by phage display and other surface display technologies such as mRNA display, ribosome display, bacterial display and yeast display. These experimental procedures are also known as biopannings. Among peptides obtained from biopannings, mimotopes can be considered as a kind of peptide aptamers. All the peptides panned from combinatorial peptide libraries have been stored in a special database with the name MimoDB.[58][59]

Selection of Ligand Regulated Peptide Aptamers (LiRPAs) has been demonstrated. By displaying 7 amino acid peptides from a novel scaffold protein based on the trimeric FKBP-rapamycin-FRB structure, interaction between the randomized peptide and target molecule can be controlled by the small molecule Rapamycin or non-immunosuppressive analogs.


X-Aptamers are a new generation of aptamers designed to improve on the binding and versatility of regular DNA/RNA- based aptamers. X-Aptamers are engineered with a combination of natural and chemically-modified DNA or RNA nucleotides. Base modifications allow incorporation of various functional groups/small molecules into X-aptamers, opening a wide range of uses and a higher likelihood of binding success compared to standard aptamers. Thiophosphate backbone modifications at selected positions enhance nuclease stability and binding affinity without sacrificing specificity.[60][61]

X-Aptamers are able to explore new features by utilizing a new selection process. Unlike SELEX, X-Aptamer selection does not rely on multiple repeated rounds of PCR amplification but rather involves a two-step bead-based discovery process. In the primary selection process, combinatorial libraries are created where each bead will carry approximately 10^12 copies of a single sequence. The beads operate as carriers, where the bound sequences will ultimately be detached into solution. In the secondary solution pull-down process, each target will be used to individually pull down the binding sequences from solution. The binding sequences are amplified, sequenced, and analyzed. Sequences that are enriched for each target can then be synthesized and characterized.[62] X-aptamers are commercially produced under the name "Raptamers" by a company called Raptamer Discovery Group.[63]




Aptamers can be used as:

Aptamers have also been generated against several pathogens both bacterial[77] & viruses including influenza A and B viruses,[78] Respiratory syncytial virus (RSV),[78] SARS coronavirus (SARS-CoV)[78] and SARS-CoV-2[79] in various experimental settings.

Antibody replacement[edit]

Aptamers have an innate ability to bind to any molecule to which they are targeted, including cancer cells and bacteria. Once bound to a target, aptamers can act as agonists or antagonists. Aptamers suffer from issues that limit their effectiveness: they're easily digested in vivo by nuclease enzymes.

Adding an unnatural base to a standard aptamer can increase its ability to bind to target molecules. A second addition in the form of a "mini hairpin DNA" gives the aptamer a stable and compact structure that is resistant to digestion, extending its life from hours to days.[80]

Aptamers are less likely to provoke undesirable immune responses than antibodies.[citation needed]

Controlled release of therapeutics[edit]

The ability of aptamers to reversibly bind molecules such as proteins has generated increasing interest in using them to facilitate controlled release of therapeutic biomolecules, such as growth factors. This can be accomplished by tuning the affinity strength to passively release the growth factors,[81] along with active release via mechanisms such as hybridization of the aptamer with complementary oligonucleotides[82] or unfolding of the aptamer due to cellular traction forces.[83]


Aptamers have been used to create hot start functions in PCR enzymes to prevent non-specific amplification during the setup and initial phases of PCR reactions.[84]

See also[edit]


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Further reading[edit]