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Reduction of herpes simplex virus type-2 replication in cell cultures and in rodent models with peptide-conjugated morpholino oligomers.
Title | Reduction of herpes simplex virus type-2 replication in cell cultures and in rodent models with peptide-conjugated morpholino oligomers. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Eide, K, Moerdyk-Schauwecker, M, Stein, DA, Bildfell, R, Koelle, DM, Jin, L |
Journal | Antivir Ther |
Volume | 15 |
Issue | 8 |
Pagination | 1141-9 |
Date Published | 2010 |
ISSN | 2040-2058 |
Keywords | Acyclovir, Animals, Antiviral Agents, Cercopithecus aethiops, Disease Models, Animal, Drug Resistance, Viral, Female, Herpes Genitalis, Herpesvirus 2, Human, Immediate-Early Proteins, Mice, Mice, Inbred BALB C, Morpholines, Morpholinos, Peptides, Recurrence, Sigmodontinae, Vero Cells, Viral Proteins, Virus Activation, Virus Replication |
Abstract | BACKGROUND: Genital herpes, caused by herpes simplex virus type-2 (HSV-2), is a recurrent, lifelong disease affecting tens of millions of people in the USA alone. HSV-2 can be treated therapeutically with acyclovir (ACV) and its derivatives; however, no treatment can prevent HSV reactivation. Novel topical anti-HSV microbicides are much needed to reduce HSV-2 transmission and to treat primary or reactivated infections, especially for ACV-resistant strains. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are single-stranded DNA analogues that enter cells readily and can reduce target gene expression through steric blockage of complementary messenger RNA (mRNA). METHODS: We investigated the antiviral activities of PPMOs targeted to the translation start-site regions of the mRNA for two HSV-2 immediate early genes, immediate early protein (ICP)0 and ICP27, and two early genes, unique long gene (UL)30 and UL39. RESULTS: In cell cultures, PPMOs targeting ICP0 or ICP27 mRNA were found to be highly effective against two strains of HSV-2, one of which was ACV-resistant. In vivo, daily topical applications of up to 1 mM ICP27 PPMO caused no gross or microscopic damage to the genital tract of uninfected BALB/c mice or cotton rats. Cotton rats receiving topical application of ICP27 PPMO 24 h after HSV-2 inoculation showed a reduction in genital lesions and a 37.5% reduction in mortality at 14 days post-infection. Mice receiving topical application of 100 μM of an ICP27 and ICP0 PPMO combination before HSV-2 inoculation had no detectable viral replication in the genital tract at 3-5 days post-infection. CONCLUSIONS: These results demonstrate that topically applied PPMOs hold promise as candidate antiviral microbicides against HSV-2 genital infection. |
DOI | 10.3851/IMP1694 |
Alternate Journal | Antivir. Ther. (Lond.) |
PubMed ID | 21149921 |