DESIGN & SYNTHESIS OF OLIGONUCLEOTIDE ANALOG ANTIVIRALS

本研究的目标是构建寡核苷酸类似物(15-25 MERS)与关键调控病毒mRNAs或Pre-RNAs互补 阻止翻译和病毒复制的mRNAs。这个 核苷单元或类似物通过取代连接 通过有机过渡金属反应生成的磷酸盐。在……里面 在某些情况下，有机金属单元将作为一部分保留 为了增强稳定性，对结构进行了改进。 该项目的具体目标可以概括为 以下是： 1)发现有机过渡金属驱动的耦合过程领先 从H-亚磷酸盐或亚磷酸盐到后来的亚磷酸盐 在温和的条件下高产。 衍生的有机金属中间体的反应 将对锰、钴、钯和铁进行调查。 这将包括金属磷键的反应。 在过渡金属和烷基亚磷酸酯之间形成， 随后可能会或可能不会重新排列成金属 亚磷酸酯络合物；烷基亚磷酸酯是 定向到过渡金属络合配体，结果是 通过间隔物附着在金属上；反应中 烷基亚磷酸酯与过渡金属络合物结合 配体，将金属从其上除去以得到烷基或 烯基膦酸盐。 2)确定了侧链的结构变化是什么 与有机金属中间体和 合成寡核苷酸所需的试剂。 3)构建一系列寡脱氧核苷酸类似物 修饰了核苷单元之间的膦酸键。 附着在磷酸盐上的侧链将被设计成 通过以下途径增强与互补mRNA序列的结合 静电相互作用。 4)抗病毒活性、生物稳定性、便携性、 人工合成寡聚脱氧核糖核酸的杂交性质 类比。

The goal of this research is to build oligonucleotide analogs (15-25 mers) complementary to key regulatory viral mRNAs or pre- mRNAs that will block translation and viral replication. The nucleoside units or the analogs are to be linked by substituted phosphonates constructed via organotransition metal reactions. In some instance the organometallic unit would be retained as part of the structure in order to enhance stability. The specific objectives of the project can be summarized as follows: 1) Find organotransition metal driven coupling processes leading from H-phosphonates or phosphites to phosphonates that proceed under the mild conditions in high yield. The reactions of organometallic intermediates derived from manganese, cobalt, palladium, and iron will be investigated. These will include reactions in which a metal phosphorus bond is formed between the transition metal and the alkyl phosphite, which may or may not subsequently rearrange to a metal phosphonate complex; reactions in which an alkyl phosphite is directed to a transition metal complexed ligand and as a result becomes attached to the metal via a spacer; reactions in which an alkyl phosphite combines with a transition metal complexed ligand, from which the metal is eliminated to give an alkyl or alkenyl phosphonate. 2) Determined what side-chain structural variations are compatible with the organometallic intermediates and the reagents necessary for oligonucleotide synthesis. 3) Build a series of oligodeoxyribonucleotide analogs with modified phosphonate linkages between nucleoside units. Side-chains attached to the phosphonates would be designed to enhance binding to complementary mRNA sequences through electrostatic interactions. 4) Test the antiviral activity, biological stability, transportability, and hybridization properties of synthetic oligodeoxyribonucleotide analogs.