Inhibition of HSV-1 ocular infection with morpholino oligomers targeting ICP0 and ICP27.
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.
Moerdyk-Schauwecker
Megan
M
Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
Stein
David A
DA
Eide
Kathleen
K
Blouch
Robert E
RE
Bildfell
Rob
R
Iversen
Patrick
P
Jin
Ling
L
D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001483:Base Sequence; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000187:drug effects*; D016849:Keratitis, Herpetic / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D008969:Molecular Sequence Data; D009025:Morpholines / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D060172:Morpholinos; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects*; D014709:Vero Cells; D014764:Viral Proteins / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; D009025:Morpholines; D060172:Morpholinos; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; D000212:Acyclovir