yDNA: a new geometry for size-expanded base pairs.
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Base Pairing↗
Biomedical subjects
Kaizhang He
Publications and source records attributed to Kaizhang He.
Reading, writing, and modulating genetic information with boranophosphate mimics of nucleotides, DNA, and RNA.
The P-boranophosphates are efficient and near perfect mimics of natural nucleic acids in permitting reading and writing of genetic information with high yield and accuracy. Substitution of a borane (-BH3) group for oxygen in the phosphate ester bond creates an isoelectronic and isosteric mimic of natural nucleotide phosphate esters found in mononucleotides, i.e., AMP and ATP, and in RNA and DNA polynucleotides. Compared to natural nucleic acids, the boranophosphate RNA and DNA analogs demonstrate increased lipophilicity and resistance to endo- and exonucleases, yet they retain negative charge and similar spatial geometry. Borane groups can readily be introduced into the NTP and dNTP nucleic acid monomer precursors to produce alpha-P-borano nucleoside triphosphate analogs (e.g., NTPalphaB and dNTPalphaB). The NTPalphaB and dNTPalphaB are, in fact, good to excellent substrates for RNA and DNA polymerases, respectively, and allow ready enzymatic synthesis of RNA and DNA with P-boranophosphate linkages. Further, boranophosphate polymer products are good templates for replication, transcription, and gene expression; boronated RNA products are also suitable for reverse transcription to cDNA. Fully substituted boranophosphate DNA can activate the RNase H cleavage of RNA in RNA:DNA hybrids. Moreover, certain dideoxy-NTPalphaB analogs appear to be better substrates for viral reverse transcriptases than the regular ddNTPs, and may offer promising prodrug alternatives in antiviral therapy. These properties make boranophosphates promising candidates for diagnostics; aptamer selection; gene therapy; and antiviral, antisense, and RNAi therapeutics. The boranophosphates constitute a versatile family of phosphate mimics for processing genetic information and modulating gene function.
Antiviral Agents↗
Boron-containing aptamers to ATP.
Boron neutron capture therapy (BNCT), an experimental treatment for certain cancers, destroys only cells near the boron; however, there is a need to develop highly specific delivery agents. As nucleic acid aptamers recognize specific molecular targets, we investigated the influence of boronated nucleotide analogs on RNA function and on the systematic evolution of ligands by exponential enrichment (SELEX) process. Substitution of guanosine 5'-(alpha-P-borano) triphosphate (bG) for GTP or uridine 5'-(alpha-P-borano) triphosphate (bU) for UTP in several known aptamers diminished or eliminated target recognition by those RNAs. Specifically, ATP-binding aptamers containing the zeta-fold, which appears in several selections for adenosine aptamers, became inactive upon bG substitution but were only moderately affected by bU substitution. Selections were carried out using the bG or bU analogs with C8-linked ATP agarose as the binding target. The selections with bU and normal NTP yielded some zeta-fold aptamers, while the bG selection yielded none of this type. Non-zeta aptamers from bU and bG populations tolerated the borano substitution and many required it. The borano nucleotide requirement is specific; bU could not be used in bG-dependent aptamers nor vice versa. The borano group plays an essential role, as yet undefined, in target recognition or RNA structure. We conclude that the bG and bU nucleotides are fully compatible with SELEX, and that these analogs could be used to make boronated aptamers as therapeutics for BNCT.
Adenosine Triphosphate↗
Synthesis and Separation of Diastereomers of Ribonucleoside 5'-(alpha-P-Borano)triphosphates.
Nucleoside boranophosphates, in which one of the phosphate oxygens is replaced by a borane group, are isoionic and isoelectronic analogues of naturally occurring nucleotides. Boranophosphates also are biochemically important congeners of phosphorothioates and methylphosphonates. We have developed a convenient one-pot method to synthesize the set of ribonucleoside (A, U, G, and C) 5'-(alpha-P-borano)triphosphates. Phosphitylation of the 2',3'-protected ribonucleoside with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one gives the 5'-phosphite intermediate 2 which undergoes in situ substitution in the presence of pyrophosphate to give the cyclic intermediate, P(2),P(3)-dioxo-P(1)-ribonucleosidylcyclotriphosphate 3. Immediate oxidation of compound 3 with amine.borane complex results in ribonucleoside 5'-(alpha-P-borano)cyclotriphosphate 4. Subsequent reaction of compound 4 with water followed by ammonium hydroxide yields the crude product as a diastereomeric mixture of ribonucleoside 5'-(alpha-P-borano)triphosphate 6. Pure compound 6 is isolated in 30-45% overall yield using ion-exchange chromatography. The separation of two diastereomers of ribonucleoside 5'-(alpha-P-borano)triphosphate 6 is achieved by reverse phase HPLC.
Journal Article↗