Direct In Vitro Selection of a 2′-O-Methyl Aptamer to VEGF

Burmeister, Paula E.; Lewis, Scott D.; Silva, Robert F.; Preiss, J.R.; Horwitz, Lillian R.; Pendergrast, P. Shannon; McCauley, Thomas G.; Kurz, Jeffrey C.; Epstein, David; Wilson, Charles B.; Keefe, Anthony D.

doi:10.1016/j.chembiol.2004.10.017

Cited by 312 publications

(226 citation statements)

References 25 publications

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“…The Ca 2ϩ requirement for the formation of the VEGF 165 -aptamer complex is specific to this aptamer family and is not observed in other high-affinity aptamers to VEGF 165 (8,(23)(24)(25). The results here show that Ca 2ϩ is also required for the HBD-aptamer complex formation.…”

Section: The Local Structure Of the Hbd-aptamer Complex Is Conserved supporting

confidence: 57%

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅

Lee

Canny²,

Erkenez³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

212

170

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Aptamers recognize their targets with extraordinary affinity and specificity. The aptamer-based therapeutic, Macugen, is derived from a modified 2 fluoro pyrimidine RNA inhibitor to vascular endothelial growth factor (VEGF) and is now being used to treat the wet form of age-related macular degeneration. This VEGF 165 aptamer binds specifically to the VEGF165 isoform, a dimeric protein with a receptor-binding domain and a heparin-binding domain (HBD). To understand the molecular recognition between VEGF and this aptamer, binding experiments were used to show that the HBD contributes the majority of binding energy in the VEGF 165-aptamer complex. A tissue culture-based competition assay demonstrated that the HBD effectively competes with VEGF165 for aptamer binding in vivo. Comparison of NMR spectra revealed that structural features of the smaller HBD-aptamer complex are present in the full-length VEGF 164-aptamer complex. These data show that the HBD provides the binding site for the aptamer and is the primary determinant for the affinity and specificity in the VEGF 165-aptamer complex.age-related macular degeneration ͉ Macugen ͉ RNA ͉ NMR

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Section: The Local Structure Of the Hbd-aptamer Complex Is Conserved supporting

confidence: 57%

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅

Lee

Canny²,

Erkenez³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

212

170

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“…RNA aptamers prepared with 2 0 -Fluoro-or 2 0 -amino pyrimidines or 2 0 -O-methyl nucleotides are highly nuclease resistant. 4 A dT-cap at the 3 0 -end can further inhibit degradation. To enhance both metabolic stability and nuclease resistance, unnatural L-nucleotides have been incorporated into aptamers, which are termed 'Spiegelmers.'…”

Section: Prospectsmentioning

confidence: 99%

Gene therapy progress and prospects: RNA aptamers

2007

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Aptamers are oligonucleotides evolved in vitro or in nature to bind target ligands with high affinity and specificity. They are emerging as powerful tools in the fields of therapeutics, drug development, target validation and diagnostics. Aptamers are attractive alternatives to antibody-and small-moleculebased therapeutics owing to their stability, low toxicity, low immunogenicity and improved safety. With the recent approval of the first aptamer drug Macugen by the US FDA, there is great impetus to develop therapeutic aptamers that can target a wide array of disease states. The recent demonstration that aptamer activity can be reversed by the administration of a simple antidote greatly enhances the potential value of aptamers as therapeutic agents.

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“…2'-amino pyrimidines, 2'-fluoropyrimidines, 2'-O-methyl ribose purines and pyrimidines, etc.) or completely substituting nucleotide [13,14]. The linkage between nucleotide can also be modified (e.g.…”

Section: Modified Aptamersmentioning

confidence: 99%

Untitled

2017

JNMR

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The aptamer is an oligonucleotide which is a short version of biological nucleic acids (such as DNA and RNA) with defined sequence of nucleotides. Based on the complexity of molecule, the aptamers lies in-between protein molecules and small chemical molecules. Aptamers have high specificity and affinity towards target proteins. They are screened from random sequences of oligonucleotides based on the highest affinity for target proteins using the SELEX (Systematic Evolution of Ligands by Exponential Enrichment). Researchers have discovered various applications of aptamers that are ready to replace the therapeutic use of biological proteins (such as antibodies) that have complexity in manufacturing and characterization. The present review describes the structural modification in aptamers such as PEGylation, substitution of functional groups, use of an enantiomeric oligonucleotide and its applications. Aptamers can be deactivated, when needed, by the use of reversal agent that contains oligonucleotide sequence complementary to aptamers. This property of aptamers makes them potential therapeutic from a safety point of view. In recent scenario, aptamers are developed for targeted drug delivery systems by conjugating with drug molecules or delivery vesicles such as liposomes. ' Anti-sense Aptamers' are being developed to silent the expression of genes responsible for the proliferative growth of tissue in cancer. Other applications of aptamers such as environmental monitoring and laboratory testing are also described in this review. Keywords: IntroductionBiotechnology based products are incredibly capturing market shares day by day. Chemistry based synthesis has a limitation when we talk about the tertiary and quaternary structure of large molecules such as protein. The human body is functioning by different biochemical reactions. Protein molecules are broadly involved in every aspect of the biological reaction. In the current paradigm, such functional proteins get expressed in microorganism by genetic variation as a part of the upstream process. Subsequently, these proteins are separated from the microorganisms and purified (as a downstream process) retaining its biological activity to inject in the human body. These complex proteins are difficult to cultivate, separate, characterize and reproduce [1,2].The basic mechanism of protein synthesis in any of the living organism involves transcription and translation of polynucleotide chain of Adenine, Guanine, Thymine, and Cytosine [3]. The sequence of the oligonucleotide is responsible for translating specific protein using a specific sequence of amino acid involved in the synthesis of protein. Currently marketed protein formulations readily provide biological action at the target site when injected into the body. Such protein molecules are produced outside of the human body and injected in purified and active form. However, the stability of proteins is the major concern in the development of protein formulations. Such biological molecules have a tertiary and qua...

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Direct In Vitro Selection of a 2′-O-Methyl Aptamer to VEGF

Cited by 312 publications

References 25 publications

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅

Gene therapy progress and prospects: RNA aptamers

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Direct In Vitro Selection of a 2′-O-Methyl Aptamer to VEGF

Cited by 312 publications

References 25 publications

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF 165

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF 165

Gene therapy progress and prospects: RNA aptamers

Untitled

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About

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅