Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer

Abstract

Certain guanine-rich (G-rich) DNA and RNA molecules can associate intermolecularly or intramolecularly to form four stranded or "quadruplex" structures, which have unusual biophysical and biological properties. Several synthetic G-rich quadruplex-forming oligodeoxynucleotides have recently been investigated as therapeutic agents for various human diseases. We refer to these biologically active G-rich oligonucleotides as aptamers because their activities arise from binding to protein targets via shape-specific recognition (analogous to antibody-antigen binding). As therapeutic agents, the G-rich aptamers may have some advantages over monoclonal antibodies and other oligonucleotide-based approaches. For example, quadruplex oligonucleotides are nonimmunogenic, heat stable and they have increased resistance to serum nucleases and enhanced cellular uptake compared to unstructured sequences. In this review, we describe the characteristics and activities of G-rich oligonucleotides. We also give a personal perspective on the discovery and development of AS1411, an antiproliferative G-rich phosphodiester oligonucleotide that is currently being tested as an anticancer agent in Phase II clinical trials. This molecule functions as an aptamer to nucleolin, a multifunctional protein that is highly expressed by cancer cells, both intracellularly and on the cell surface. Thus, the serendipitous discovery of the G-rich oligonucleotides also led to the identification of nucleolin as a new molecular target for cancer therapy. KeywordsAS1411; aptamer; G-rich oligonucleotides; quadruplex; G-quartets; nucleolin; NF-kappaB; PRMT5; T-oligos; Dz13 Oligonucleotides as Therapeutic AgentsSince automated DNA synthesizers became widely available in the 1980s, there has been substantial interest in developing synthetic oligonucleotides for use as therapeutic agents [1][2][3][4][5][6][7][8][9]. Initial strategies aimed to prevent translation or transcription of specific viral or cellular * To whom correspondence should be addressed: 580 S. Preston St., Louisville, Kentucky 40202; Phone: (502) 852 2432; Email: E-mail: paula.bates@louisville.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of Interest Statement:Some of the authors (PJB, JOT, DMM) are inventors of patented or patent-pending technologies related to AS1411, G-rich oligonucleotides and nucleolin. Some of the authors (PJB, JOT, DMM) are shareholders in Antisoma, the company that is now sponsoring the development of AS1411. In addition, PJB is presently a recipient of grant support from Antisoma on projects related to AS14...

RNA-binding protein nucleolin in disease

“…The promising effects of this aptamer have led to several clinical trials in patients with advanced solid tumors. 138 Nucleolin-directed anticancer peptides. As explained above, the synthetic peptide HB-19 specifically antagonizes the C-terminal RGG domain of nucleolin and inhibits cell membrane-associated nucleolin function, thereby preventing the growth, angiogenesis and tumorigenicity of numerous cancer cells using different assays.…”

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

“…Guanine-rich (G-rich) oligonucleotides (ODNs) have the potential to assemble intra-or intermolecular G-quadruplex (G4) structures that are resistant to nucleases, and they spontaneously enter cells by a poorly characterized mechanism (13)(14)(15). Here, we show that biologically active 5′-tiRNA Ala and 5′-tiRNA Cys form…”

Structure of a left-handed DNA G-quadruplex

“…Recent studies demonstrated their existence in human cells (15) and their involvement in cellular regulation including recombination (12), replication (13,14), transcription (10), and translation (11). On the other hand, synthetic G4s have been introduced as unique structural elements in nanotechnology (20) as well as aptamers for therapeutic and diagnostic purposes (21). For instance, the G-rich oligonucleotide AGRO100 (SI Appendix, Table S1), also known as AS1411, has been shown to exhibit potent antiproliferative activity against a range of cancer cells (21) and was later found to adopt multiple G4 conformations (22).…”