与前导RNA互补的修饰寡核苷酸对小鼠肝炎病毒增殖的抑制作用

Inhibitory effects of modified oligonucleotides complementary to the leader RNA on the multiplication of mouse hepatitis virus.

作者信息

Hayashi M, Maeda A, Kihara M, Arai S, Hanaki K, Nozaki T

机构信息

Department of Veterinary Radiology, Rakuno Gakuen University, Ebetsu, Japan.

出版信息

Adv Exp Med Biol. 1998;440:701-5. doi: 10.1007/978-1-4615-5331-1_90.

DOI:10.1007/978-1-4615-5331-1_90

PMID:9782347

Abstract

Phosphorothioate oligonucleotides (PS-oligo) and PS-oligos with cholesterol conjugates (ChPS-oligo) complementary to the leader RNA of strain JHM of mouse hepatitis virus (JHMV) were more effective inhibitors of viral multiplication than natural oligodeoxynucleotides (PO-oligo) in JHMV-infected DBT cells. PS- and ChPS-oligos were 1,000 times more potent than unmodified PO-oligo. No significant difference was observed in the inhibitory efficiency between PS-oligo and ChPS-oligo. Sequence-dependent inhibition of viral multiplication was shown at low concentrations (0.001-0.1 M) of antisense PS-oligo and ChPS-oligo. Phosphorothioate oligodeoxycytidine, PS-(dC)20, and PS-(dC)20 with cholesterol conjugates, and PS- and ChPS-oligo which have no significant homology to the JHMV sequences, showed inhibitory effects on JHMV multiplication at concentrations higher than 0.5 M. These results showed that PS-oligo and ChPS-oligo were more potent than PO-oligo in the inhibition of JHMV multiplication, and that PS-oligo and ChPS-oligo may inhibit JHMV multiplication by two different mechanisms, that is by sequence-dependent and sequence-independent manners.

摘要

硫代磷酸寡核苷酸（PS - 寡核苷酸）以及与小鼠肝炎病毒（JHMV）JHM株前导RNA互补的带有胆固醇共轭物的PS - 寡核苷酸（ChPS - 寡核苷酸），在JHMV感染的DBT细胞中，比天然寡脱氧核苷酸（PO - 寡核苷酸）更有效地抑制病毒增殖。PS - 寡核苷酸和ChPS - 寡核苷酸的效力比未修饰的PO - 寡核苷酸高1000倍。在PS - 寡核苷酸和ChPS - 寡核苷酸之间未观察到抑制效率的显著差异。在低浓度（0.001 - 0.1 M）的反义PS - 寡核苷酸和ChPS - 寡核苷酸下显示出对病毒增殖的序列依赖性抑制。硫代磷酸寡脱氧胞苷、PS - (dC)20以及带有胆固醇共轭物的PS - (dC)20，还有与JHMV序列无显著同源性的PS - 寡核苷酸和ChPS - 寡核苷酸，在浓度高于0.5 M时对JHMV增殖显示出抑制作用。这些结果表明，PS - 寡核苷酸和ChPS - 寡核苷酸在抑制JHMV增殖方面比PO - 寡核苷酸更有效，并且PS - 寡核苷酸和ChPS - 寡核苷酸可能通过两种不同机制抑制JHMV增殖，即通过序列依赖性和序列非依赖性方式。