2′-Fluoropyrimidine RNA-based Aptamers to the 165-Amino Acid Form of Vascular Endothelial Growth Factor (VEGF165)

Ruckman, Judy; Green, Louis S.; Beeson, Jim; Waugh, Sheela; Gillette, Wendy L.; Henninger, Dwight; Claesson‐Welsh, Lena; Janjić, Nebojša

doi:10.1074/jbc.273.32.20556

Cited by 660 publications

(309 citation statements)

References 71 publications

(91 reference statements)

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“…No binding to the HBD was observed in the absence of Ca 2ϩ . Previous studies showed that calcium ions are also required for aptamer binding to full-length VEGF 165 where no binding was observed with Mg 2ϩ (8).…”

Section: The Vegf Aptamer Forms a Specific Complex With The Hbd Of Vementioning

confidence: 99%

“…This aptamer binds to VEGF 165 with extremely high affinity (K d ϭ 50 pM), and animal studies and clinical data have demonstrated the efficacy of the aptamer in preventing blood vessel growth and arresting the progression of wet AMD (8,(11)(12)(13)(14). However, the detailed molecular mechanism by which this aptamer achieves isoform-specific inhibition of VEGF 165 is not well understood.…”

mentioning

confidence: 99%

“…However, the detailed molecular mechanism by which this aptamer achieves isoform-specific inhibition of VEGF 165 is not well understood. An efficient photo-crosslink has been obtained between the HBD and the aptamer, suggesting this aptamer recognizes VEGF 165 by targeting the HBD (8). The focus of the studies here is to characterize the role of the HBD in isoform-specific recognition of VEGF 165 by the aptamer.…”

mentioning

confidence: 99%

“…These antibodies inhibit all isoforms of VEGF. In contrast, a nucleic acid-based inhibitor, Macugen, currently used in treatment of wet AMD (5) is an isoform-specific inhibitor of VEGF 165 that does not recognize VEGF 121 , which lacks the HBD (8).…”

mentioning

confidence: 99%

“…1A). For effective treatment of AMD in humans, the aptamer is further modified with a 5Ј polyethyleneglycol moiety and a 3Ј dT attached via a 3Ј-3Ј linkage to confer favorable pharmacokinetic properties and for protection against exonucleases (8).…”

mentioning

confidence: 99%

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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.

208

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 Vegf Aptamer Forms a Specific Complex With The Hbd Of Vementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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.

208

170

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Intravitreal Bevacizumab vs Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degeneration

Bashshur

Schakal²,

Hamam³

et al. 2007

Arch Ophthalmol

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Comparing Pegaptanib and Triamcinolone Efficacy in the Rat Choroidal Neovascularization Model

Criswell

Hu²,

Steffens³

et al. 2008

Arch Ophthalmol

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To evaluate the prophylactic effect of intravitreal pegaptanib sodium on choroidal neovascularization membrane (CNVM) development and compare its performance with that of triamcinolone acetonide. Methods: In drug-treated and control groups, CNVMs were induced by laser trauma. Immediately after undergoing the laser procedure, animals received intravitreal injections of pegaptanib sodium, 8 or 17 µg; triamcinolone acetonide, 200 µg; or a vehicle solution. After 21 days, fluorescein angiography was performed. The CNVM mean diameters and radial thicknesses were measured histologically. Results: Mean CNVM diameters were 10% to 13% smaller in pegaptanib-treated eyes and 43% smaller in triamcinolone-treated eyes compared with laser-only control eyes. Late-stage fluorescein angiography leakage scores, on a scale of 0 to 3, suggested a statistical difference between triamcinolone-(0.6) and pegaptanib 8 µg-treated (1.5) groups compared with the laser-only control group (2.0). The CNVM mean thicknesses were greater in the pegaptanib 8 µg-(79 µm) and pegaptanib 17 µg-treated (71 µm) groups and significantly smaller in the triamcinolonetreated group (26 µm) compared with the laser-only control group (67 µm). Conclusion: In this animal model of choroidal neovascularization, intravitreal pegaptanib exhibited marginal or no effect on CNVM development; whereas intravitreal triamcinolone evoked robust inhibition of CNVMs. Clinical Relevance: Pegaptanib treatment may be insufficient to prevent CNVM formation.

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2′-Fluoropyrimidine RNA-based Aptamers to the 165-Amino Acid Form of Vascular Endothelial Growth Factor (VEGF165)

Cited by 660 publications

References 71 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

Intravitreal Bevacizumab vs Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degeneration

Comparing Pegaptanib and Triamcinolone Efficacy in the Rat Choroidal Neovascularization Model

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2′-Fluoropyrimidine RNA-based Aptamers to the 165-Amino Acid Form of Vascular Endothelial Growth Factor (VEGF165)

Cited by 660 publications

References 71 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

Intravitreal Bevacizumab vs Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degeneration

Comparing Pegaptanib and Triamcinolone Efficacy in the Rat Choroidal Neovascularization Model

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Resources

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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