Gao W Y, Stein C A, Cohen J S, Dutschman G E, Cheng Y C
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599-7365.
J Biol Chem. 1989 Jul 5;264(19):11521-6.
Effects of phosphorothioate oligodeoxynucleotides of different chain length and base composition on herpes simplex virus (HSV) type 2 (strain 333)-induced DNA polymerase have been examined in vitro. The anti-HSV-2 DNA polymerase activity was related to the base composition of the analogs, with the order of potency: deoxycytidine greater than thymidine greater than deoxyadenosine, for compounds with equal chain length. The potency was also related to oligomer chain length, since it was observed that the longer the chain length, the more potent the inhibition exerted. Among all the compounds tested, the phosphorothioate oligodeoxycytidine 28-mer (S-(dC)28) was the most potent inhibitor of HSV-2-induced DNA polymerase. This inhibition was competitive with an activated DNA template with a Ki value of 7 nM. It was also a competitive inhibitor of the DNA polymerase-associated exonuclease activity with a Ki value of 5 nM. In contrast, this compound showed less inhibition of human DNA polymerase alpha, beta, and gamma, as well as HSV-1 (strain KOS) and Epstein-Barr virus-induced DNA polymerase. The possibility that S-oligomers can serve as primers for DNA elongation was also investigated. Poly(dG).S-(dC)28 and poly(dA).S-(T)28 are poor substrates for DNA elongation catalyzed by HSV-2 DNA polymerase. In summary, phosphorothioate oligonucleotides could be anti-template inhibitors of HSV DNA polymerase. This information may lead to the development of a new class of selective anti-HSV agents.
在体外研究了不同链长和碱基组成的硫代磷酸酯寡脱氧核苷酸对2型单纯疱疹病毒（HSV）（333株）诱导的DNA聚合酶的影响。抗HSV-2 DNA聚合酶活性与类似物的碱基组成有关，对于链长相等的化合物，其效力顺序为：脱氧胞苷＞胸苷＞脱氧腺苷。效力也与寡聚物链长有关，因为观察到链长越长，抑制作用越强。在所有测试的化合物中，硫代磷酸酯寡脱氧胞苷28聚体（S-(dC)28）是HSV-2诱导的DNA聚合酶的最有效抑制剂。这种抑制作用与活化的DNA模板竞争，Ki值为7 nM。它也是DNA聚合酶相关核酸外切酶活性的竞争性抑制剂，Ki值为5 nM。相比之下，该化合物对人DNA聚合酶α、β和γ以及HSV-1（KOS株）和爱泼斯坦-巴尔病毒诱导的DNA聚合酶的抑制作用较小。还研究了S-寡聚物作为DNA延伸引物的可能性。聚（dG）.S-(dC)28和聚（dA）.S-(T)28是HSV-2 DNA聚合酶催化的DNA延伸的不良底物。总之，硫代磷酸酯寡核苷酸可能是HSV DNA聚合酶的抗模板抑制剂。这一信息可能会导致开发出一类新型的选择性抗HSV药物。
