Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Department of Chemistry, Analytical & Biological Chemistry Research Facility, Synthesis & Solid State Pharmaceutical Centre, University College, Cork, Ireland.
Future Med Chem. 2019 Jan;11(2):137-154. doi: 10.4155/fmc-2018-0324. Epub 2019 Jan 16.
Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2'-deoxynucleotide 5'-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.
无环核苷膦酸酯代表了一类已被临床应用的明确的核苷类似物。所有无环核苷膦酸酯在与病毒 DNA 聚合酶结合之前都需要细胞内磷酸化。最近，一类新型的α-羧基核苷膦酸酯被设计用来模拟 DNA 聚合酶的天然 2'-脱氧核苷酸 5'-三磷酸底物。它们在膦酸部分含有一个通过环状或无环桥与碱基相连的羧基。α-羧基核苷膦酸酯不需要任何代谢转化即可作为病毒 DNA 聚合酶抑制剂发挥作用。已经证明了对逆转录病毒逆转录酶和疱疹病毒 DNA 聚合酶的选择性抑制活性。这些化合物具有独特的抑制病毒 DNA 聚合酶的机制，为进一步修饰以优化和微调其抗病毒 DNA 聚合酶谱提供了可能性。
