Moerdyk-Schauwecker Megan, Stein David A, Eide Kathleen, Blouch Robert E, Bildfell Rob, Iversen Patrick, Jin Ling
Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
Antiviral Res. 2009 Nov;84(2):131-41. doi: 10.1016/j.antiviral.2009.07.020. Epub 2009 Aug 7.
Alternative therapies are needed for HSV-1 infections in patients refractory to treatment with Acyclovir (ACV) and its derivatives. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are single-stranded DNA analogues that enter cells readily and reduce target gene expression through steric blockage of complementary RNA. When applied before or soon after infection PPMO targeting the translation-start-site regions of HSV-1 ICP0 or ICP27 mRNA reduced HSV-1 plaque formation by 70-98% in vitro. The ICP0 PPMO also reduced ACV-resistant HSV-1 (strain 615.9) plaque formation by 70-90%, while an equivalent dose of ACV produced only 40-50% inhibition when the treatment was applied between 1 and 3hpi. Seven daily topical treatments of 100microg ICP0 PPMO caused no gross or microscopic damage to the corneas of uninfected mice. Topical application of 10microg ICP0 PPMO to the eyes of HSV-1 infected mice reduced the incidence of eye disease by 37.5-50% compared to controls. This study demonstrates that topically applied PPMO holds promise as an antiviral drug candidate against HSV-1 ocular infection.
对于用阿昔洛韦（ACV）及其衍生物治疗无效的单纯疱疹病毒1型（HSV-1）感染患者，需要替代疗法。肽缀合的磷酰胺吗啉代寡聚物（PPMO）是单链DNA类似物，可轻易进入细胞并通过空间位阻互补RNA来降低靶基因表达。在感染前或感染后不久应用靶向HSV-1 ICP0或ICP27 mRNA翻译起始位点区域的PPMO，可在体外使HSV-1蚀斑形成减少70-98%。ICP0 PPMO还使耐ACV的HSV-1（615.9株）蚀斑形成减少70-90%，而当在感染后1至3小时之间进行治疗时，同等剂量的ACV仅产生40-50%的抑制作用。每天局部应用100μg ICP0 PPMO进行七次治疗，对未感染小鼠的角膜未造成肉眼可见或显微镜下的损伤。与对照组相比，向HSV-1感染小鼠的眼睛局部应用10μg ICP0 PPMO可使眼病发病率降低37.5-50%。这项研究表明，局部应用PPMO有望成为抗HSV-1眼部感染的抗病毒候选药物。
