Abstract:In this study, chemical modification of 2′-deoxyinosine (2′-dI) and D-/L-isothymidine (D-/L-isoT) was performed on AS1411. They could promote the nucleotide-protein interaction by changing the local conformation. Twenty modified sequences were obtained, FCL-I and FCL-II showed the most noticeable activity improvement. They stabilized the G-quadruplex, remained highly resistant to serum degradation and specificity for nucleolin, further inhibited tumor cell growth, exhibited a stronger ability to influence the … Show more
“…The obtained K D values for the binding interaction between the free AS1411 aptamer and the AS1411-C 8 complex with nucleolin were 8.63 pM and 6.38 pM, respectively. The obtained K D values are lower than those reported in the literature, being potentially overestimated by the use of labelled oligonucleotides or the use of a different peptide than that used in those studies 28,29 . Nonetheless, both values are in the same range, being slightly lower in the case of the aptamer-ligand complex which suggests that the ligand does not negatively affect the recognition of the protein by the aptamer.Figure 8Saturation binding plots fitted to Michaelis-Menten model.…”
AS1411 is a G-rich DNA oligonucleotide that functions as an aptamer of the protein nucleolin, found at high levels on the surface of cancer cells but not on the surface of normal cells. Herein, we have studied AS1411 as a supramolecular carrier for the delivery of an acridine-based G-quadruplex ligand, C
8
, to HeLa cancer cells. Two AS1411 derivatives, LNA-AS1411 and U-AS1411, were also tested, in an attempt to compare AS1411 pharmacological properties. The results showed that AS1411-C
8
complexation was made with great binding strength and that it lowered the ligand’s cytotoxicity towards non-malignant cells. This effect was suggested to be due to a decreased internalization of the complexed versus free C
8
as shown by flow cytometry. The AS1411 derivatives, despite forming a stable complex with C
8
, lacked the necessary tumour-selective behaviour. The binding of C
8
to AS1411 G-quadruplex structure did not negatively affect the recognition of nucleolin by the aptamer. The AS1411-C
8
repressed c-MYC expression at the transcriptional level, possibly due to C
8
ability to stabilize the c-MYC promoter G-quadruplexes. Overall, this study demonstrates the usefulness of AS1411 as a supramolecular carrier of the G-quadruplex binder C
8
and the potential of using its tumour-selective properties for the delivery of ligands for cancer therapy.
“…The obtained K D values for the binding interaction between the free AS1411 aptamer and the AS1411-C 8 complex with nucleolin were 8.63 pM and 6.38 pM, respectively. The obtained K D values are lower than those reported in the literature, being potentially overestimated by the use of labelled oligonucleotides or the use of a different peptide than that used in those studies 28,29 . Nonetheless, both values are in the same range, being slightly lower in the case of the aptamer-ligand complex which suggests that the ligand does not negatively affect the recognition of the protein by the aptamer.Figure 8Saturation binding plots fitted to Michaelis-Menten model.…”
AS1411 is a G-rich DNA oligonucleotide that functions as an aptamer of the protein nucleolin, found at high levels on the surface of cancer cells but not on the surface of normal cells. Herein, we have studied AS1411 as a supramolecular carrier for the delivery of an acridine-based G-quadruplex ligand, C
8
, to HeLa cancer cells. Two AS1411 derivatives, LNA-AS1411 and U-AS1411, were also tested, in an attempt to compare AS1411 pharmacological properties. The results showed that AS1411-C
8
complexation was made with great binding strength and that it lowered the ligand’s cytotoxicity towards non-malignant cells. This effect was suggested to be due to a decreased internalization of the complexed versus free C
8
as shown by flow cytometry. The AS1411 derivatives, despite forming a stable complex with C
8
, lacked the necessary tumour-selective behaviour. The binding of C
8
to AS1411 G-quadruplex structure did not negatively affect the recognition of nucleolin by the aptamer. The AS1411-C
8
repressed c-MYC expression at the transcriptional level, possibly due to C
8
ability to stabilize the c-MYC promoter G-quadruplexes. Overall, this study demonstrates the usefulness of AS1411 as a supramolecular carrier of the G-quadruplex binder C
8
and the potential of using its tumour-selective properties for the delivery of ligands for cancer therapy.
“…Multiple mapping and functional studies have revealed important roles of G-quadruplex structures in the regulation of gene expression and transcription, protein translation and proteolysis, DNA repair, maintenance of the stability of chromosome ends, and epigenetic regulation [2,3,4,5,6,7]. For now, many selective G-quadruplex ligands show potential for antitumor therapy applications by causing DNA damage responses and growth arrest in human cancer cells [8,9,10,11,12].…”
G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.
“…G-quadruplex (G4) was first discovered by Gellert et al In 1962, G-quadruplex is composed of DNA or RNA strands rich in serially repeated guanine (G) [ 39 ] induced by metal ions, and under certain ionic strength and appropriate pH conditions, It is a special secondary structure of nucleic acid formed by the accumulation of tetrad structure formed by Hoogsteen hydrogen bond [ 40 ], and it is also the supra-molecular structure of G-rich nucleic acid [ 41 – 44 ]. Advances in the chemical and structural biology of G-quadruplex have enabled the design of specific G4 aptamers to be used as novel anticancer agents and suitable for clinical trials [ 45 ].…”
Targeted cancer therapy has become one of the most important medical methods because of the spreading and metastatic nature of cancer. Based on the introduction of AS1411 and its four-chain structure, this paper reviews the research progress in cancer detection and drug delivery systems by modifying AS1411 aptamers based on graphene, mesoporous silica, silver and gold. The application of AS1411 in cancer treatment and drug delivery and the use of AS1411 as a targeting agent for the detection of cancer markers such as nucleoli were summarized from three aspects of active targeting, passive targeting and targeted nucleic acid apharmers. Although AS1411 has been withdrawn from clinical trials, the research surrounding its structural optimization is still very popular. Further progress has been made in the modification of nanoparticles loaded with TCM extracts by AS1411.
Graphical Abstract
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