A new class of modified nucleic acids, the oligodeoxynucleoside boranophosphates (BH3-ODN), are isoelectronic and iso-ionic analogs of the phosphorothioates and the naturally occurring O-phosphate esters. Studies demonstrate that HB3-ODN possess unique properties and have potential for application as diagnostic and therapeutic agents. Relative to normal DNA, BH3--ODN have increased lipophilicity and are notably resistant to degradation by nucleases. Preliminary data suggest that BH3--ODN support RNAse H induced cleavage of RNA. BH3--ODN can by synthesized enzymatically to give gene-length fragments that are accurate, complementary copies of the parent DNA. A promising new chemical method for synthesizing BH3--ODN is currently being explored. Further applications are planned for solution phase chemistries to solid phase synthesis, making possible for the first time the synthesis of lon oligos with defined sequence, at up to millimolar scale. Other goals of the proposed work are to examine further the unique chemical and biological properties of the boranophosphate oligomers, and develop a novel set of boronated compounds for practical use.
The specific aims are to: 1)Develop effective chemical and enzymatic approaches to expedite synthesis of the BH3--ODN of any given length and sequence, in conjunction with appropriate analytical methods to verify the BH3--ODN integrity, base composition, sequence, and length. 2)Investigate and delineate the chemical, biochemical, and biophysical properties of BH3--ODN which are most essential for biochemica and therapeutical applications, including their stability under physiological conditions, nuclease resistance, lipophilicity and ability to cross cell membranes, metabolism, and their ability to form duplexes and triplexes with the complementary DNA and RNA. 3)Examine the potential of BH3--ODN for activating RNAse H in vitro and for arresting translation and transcription. 4 Conjugate BH3--ODN with appropriate functional groups (peptides, phospholipids fluoresce labels, etc.) to facilitate their cell penetration and targeting to specific cell types, and to examine their cell localization. 5) Study the feasibility of employing BH3--ODN to target human viral and genetic diseases. Results will be compared with other modified ODN. Thus, boranophosphates represent and exciting new chemistry on which to build new diagnostic and therapeutic technologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057693-02
Application #
2910436
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1998-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Xu, Zhihong; Shaw, Barbara Ramsay (2015) Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine ?-P-Borano-?-P-N-l-tryptophanyltriphosphates. Molecules 20:18808-26
Shaw, Barbara Ramsay; Moussa, Laura; Sharaf, Mariam et al. (2008) Boranophosphate siRNA-aptamer chimeras for tumor-specific downregulation of cancer receptors and modulators. Nucleic Acids Symp Ser (Oxf) :655-6
Liu, Hongyan; Hashmi, Syed N; Shaw, Barbara Ramsay (2007) Synthesis of 9-fluorenemethyl boranophosphonodiphosphate via an H-phosphonate approach. Nucleosides Nucleotides Nucleic Acids 26:1455-7
Li, Ping; Sergueeva, Zinaida A; Dobrikov, Mikhail et al. (2007) Nucleoside and oligonucleoside boranophosphates: chemistry and properties. Chem Rev 107:4746-96
Hall, Allison H S; Wan, Jing; Spesock, April et al. (2006) High potency silencing by single-stranded boranophosphate siRNA. Nucleic Acids Res 34:2773-81
Khan, Shoeb I; Dobrikov, Mikhail I; Shaw, Barbara Ramsay (2005) Synthesis of 5-ethynyl-2'-deoxyuridine-5'-boranomono phosphate as a potential thymidylate synthase inhibitor. Nucleosides Nucleotides Nucleic Acids 24:1047-9
Wang, Joy Xin; Sergueev, Dmitri S; Shaw, Barbara Ramsay (2005) The effect of a single boranophosphate substitution with defined configuration on the thermal stability and conformation of a DNA duplex. Nucleosides Nucleotides Nucleic Acids 24:951-5
Wan, Jing; Shaw, Barbara Ramsay (2005) Incorporation of ribonucleoside 5'-(alpha-P-borano)triphosphates into a 20-mer RNA by T7 RNA polymerase. Nucleosides Nucleotides Nucleic Acids 24:943-6
Summers, Jack S; Base, Karel; Boukhalfa, Hakim et al. (2005) Use of phosphorus ligand NMR probes to investigate electronic and second-sphere solvent effects in ligand substitution reactions at manganese(II) and manganese(III). Inorg Chem 44:3405-11
Wang, Joy Xin; Shaw, Barbara Ramsay (2005) Synthesis of 5-(1-propynyl)-2'-deoxyuridine 5'-(alpha-P-borano)triphosphate and kinetic characterization as a substrate for mmlv reverse transcriptase. Nucleosides Nucleotides Nucleic Acids 24:947-50

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