Inhibition of alphavirus infection in cell culture and in mice with antisense morpholino oligomers.
The genus Alphavirus contains members that threaten human health, both as natural pathogens and as potential biological weapons. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) enter cells readily and can inhibit viral replication through sequence-specific steric blockade of viral RNA. Sindbis virus (SINV) has low pathogenicity in humans and is regularly utilized as a model alphavirus. PPMO targeting the 5'-terminal and AUG translation start site regions of the SINV genome blocked the production of infectious SINV in tissue culture. PPMO designed against corresponding regions in Venezuelan equine encephalitis virus (VEEV) were likewise found to be effective in vitro against several strains of VEEV. Mice treated with PPMO before and after VEEV infection were completely protected from lethal outcome while mice receiving only post-infection PPMO treatment were partially protected. Levels of virus in tissue samples correlated with animal survival. Uninfected mice suffered no apparent ill-effects from PPMO treatment. Thus, PPMO appear promising as candidates for therapeutic development against alphaviruses.
Paessler
Slobodan
S
Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019, USA. slpaessl@utmb.edu
Rijnbrand
Rene
R
Stein
David A
DA
Ni
Haolin
H
Yun
Nadezhda E
NE
Dziuba
Natallia
N
Borisevich
Viktoriya
V
Seregin
Alexey
A
Ma
Yinghong
Y
Blouch
Robert
R
Iversen
Patrick L
PL
Zacks
Michele A
MA
D000281:Administration, Intranasal; D000524:Alphavirus / Q000187:drug effects* / Q000235:genetics; D018354:Alphavirus Infections / Q000517:prevention & control* / Q000821:virology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015195:Drug Design; D004666:Encephalitis Virus, Venezuelan Equine / Q000187:drug effects; D004685:Encephalomyelitis, Venezuelan Equine / Q000517:prevention & control; D007279:Injections, Subcutaneous; D051379:Mice; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use*; D060172:Morpholinos; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use*; D012845:Sindbis Virus / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication
D000998:Antiviral Agents; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense