Abstract
Aptamers can be chemically modified to enhance nuclease resistance and increase target affinity. In this study, we performed chemical modification of 2′-deoxyinosine in AS1411, an anti-proliferative G-rich oligodeoxynucleotide aptamer, which binds selectively to the nucleolin protein. Its function was augmented when 2′-deoxyinosine was incorporated at positions 12, 13, 15, and 24 of AS1411, respectively. In addition, double incorporation of 2′-deoxyinosine at positions 12 and 24 (FAN-1224dI), 13 and 24 (FAN-1324dI), and 15 and 24 (FAN-1524dI) promoted G-quartet formation, as well as inhibition of DNA replication and tumor cell growth, and induced S-phase cell cycle arrest. In further animal experiments, FAN-1224dI, FAN-1324dI and FAN-1524dI resulted in enhanced treatment effects than AS1411 alone. These results suggested that the position and number of modification substituents in AS1411 are critical parameters to improve the diagnostic and therapeutic function of the aptamer. Structural investigations of the FAN-1524dI/nucleolin complex structure, using molecular dynamics simulation, revealed the critical interactions involving nucleolin and 2′-dI incorporated AS1411 compared with AS1411 alone. These findings augment understanding of the role of 2′-deoxyinosine moieties in interactive binding processes.
Highlights
Aptamers can be chemically modified to enhance nuclease resistance and increase target affinity
AS1411 (Fig. 1A) is a 26-base guanine-rich oligonucleotides (GROs) which targets nucleolin, a nuclear matrix protein found on the surface of many kinds of cancer cells and whose levels are known to be associated with the rate of malignant proliferation[6], being elevated in rapidly dividing cells
We tested the effects of 2′-dI-modified AS1411 on the growth of MCF-7 cells in culture
Summary
Aptamers can be chemically modified to enhance nuclease resistance and increase target affinity. FAN-1224dI, FAN-1324dI and FAN-1524dI resulted in enhanced treatment effects than AS1411 alone These results suggested that the position and number of modification substituents in AS1411 are critical parameters to improve the diagnostic and therapeutic function of the aptamer. Structural investigations of the FAN-1524dI/nucleolin complex structure, using molecular dynamics simulation, revealed the critical interactions involving nucleolin and 2′-dI incorporated AS1411 compared with AS1411 alone These findings augment understanding of the role of 2′-deoxyinosine moieties in interactive binding processes. Scuotto[5] reported that site-specific replacements of a single-loop nucleoside with a dibenzyl linker in the TBA sequence can preserve its anti-proliferative over anticoagulant activity Taken together, these findings mean that suitable chemical modifications play important roles in aptamer studies. At least three compounds with Cy3-labeled 5-(N-benzylcarboxyamide)-2′-deoxyuridine (5-BzdU) modification exhibited significantly increased targeting affinity to C6 cells[10]
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