Oligonucleotide antiviral therapeutics: antisense and RNA interference for highly pathogenic RNA viruses.
RNA viruses are a significant source of morbidity and mortality in humans every year. Additionally, the potential use of these viruses in acts of bioterrorism poses a threat to national security. Given the paucity of vaccines or postexposure therapeutics for many highly pathogenic RNA viruses, novel treatments are badly needed. Sequence-based drug design, under development for almost 20 years, is proving effective in animal models and has moved into clinical trials. Important advances in the field include the characterization of RNA interference in mammalian cells and chemical modifications that can dramatically increase the in vivo stability of therapeutic oligonucleotides. Antisense strategies utilize single-stranded DNA oligonucleotides that inhibit protein production by mediating the catalytic degradation of target mRNA, or by binding to sites on mRNA essential for translation. Double-stranded RNA oligonucleotides, known as short-interfering RNAs (siRNAs), also mediate the catalytic degradation of complementary mRNAs. As RNA virus infection is predicated on the delivery, replication, and translation of viral RNA, these pathogens present an obvious target for the rapidly advancing field of sequence-specific therapeutics. Antisense oligonucleotides or siRNAs can be designed to target the viral RNA genome or viral transcripts. This article reviews current knowledge on therapeutic applications of antisense and RNA interference for highly pathogenic RNA viral infections.
Spurgers
Kevin B
KB
United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702, USA. kevin.spurgers@us.army.mil
Sharkey
C Matthew
CM
Warfield
Kelly L
KL
Bavari
Sina
S
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D060172:Morpholinos; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D012327:RNA Virus Infections / Q000188:drug therapy* / Q000821:virology; D012328:RNA Viruses / Q000187:drug effects* / Q000472:pathogenicity; D034741:RNA, Small Interfering / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism
D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D012367:RNA, Viral