Aptamer Design

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Aptamers Technical Information

Smart Designed Aptamers by Gene Link
Gene Link presents various design options for synthesizing effective aptamers based on the application. Smart Designed Aptamers can be synthesized in a predetermined way to exhibit the features that is desired; for instance to increase cellular delivery we may add cholesterol to the synthetic aptamer oligonucleotide sequence or add a short peptide sequence that is known to aid in transport of the aptamer to the nucleus.
Aptamers have received widespread recognition as an alternate to the use of antibody based protocols. Aptamers are very stable as compared to antibodies, are chemically stable more stable, can withstand more harsh environmental conditions and can be boiled or frozen without loss of activity. Production methods are less demanding and are synthetically produced. The production can be easily scaled up to kilogram quantities for therapeutic applications with minimal lot to lot variations. As with most natural molecules these are prone to degradation under normal conditions, specifically once introduced in body fluids. Ubiquitous nucleases well as chemical instability lead to fast degradation with a finite half life.
The premise of this product guide is to discuss various modifications that are offered by Gene Link that may be used for aptamer modification based on application. There are four common features that are desirable and in particular can be improved by using a combination of available nucleic acid modifications that modify the phosphodiester linkages, nucleic acid bases, the sugar moieties and addition of various other functional groups.
Common Features for Improvement
1. Increased duplex stability and manipulation of duplex stability.
2. Increased nuclease resistance.
3. Cellular delivery.
4. Surface attachment.
Increased Duplex Stability and Manipulation of Duplex Stability
The folding of single stranded nucleic acids in a particular shape leads to its interaction with the target molecule. Successful interactions are those where the nucleic acid ligand –Aptamer binding to the target leads to overall stability of the structural conformation of the specific aptamer. There will be a pool of such aptamers for a particular target molecule. This pool of specific aptamers differ in their dissociation constant and this is directly related to its three dimensional shape. The shape is due to its sequence and in turn to the intra-molecular hybridization. Manipulation of this sequence to increase the duplex stability or in some cases to decrease the duplex stability in certain loop structure will lead to aptamers with increased affinity for the target molecule. There are many nucleic acid modifiers that increase duplex stability, examples are 5-methyl dC, 2-amino dA, locked nucleic acids etc.
Increased Nuclease Resistance
Nucleic acids are degraded rapidly once introduced in bodily fluids, RNA are more susceptible to degradation under normal laboratory conditions particularly due to RNase contamination. Special precautions must be taken to prevent RNA degradation. Nuclease resistant modifications can be introduced chemically in oligonucleotides that still retain its molecular structure and its shape based molecular interaction. These modifications are almost indispensable and have been used intensely in antisense applications. Also nucleic acids with mirror image chemistry have been developed that evade natural nucleases completely. Examples are converting the normal phosphodiester linkages to phosphorothioate or phosphorodithioate linkages, 2’O methyl, propyne bases etc.

Cellular Delivery
Cellular delivery is an important functional aspect for therapeutic aptamers in addition to duplex stability and nuclease resistance. Polyethylene glycol, cholesterol, and various peptide structures have been used to attach to aptamers to facilitate cellular delivery or even targeting to the nucleus. Photo-cleavable linkers have been used that can be cleaved under controlled conditions.

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