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Seeking MRNA Methylation Inhibitors as Antiviral Agents


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dc.contributor.advisorSchneller, Stewart
dc.contributor.advisorLivant, Peteren_US
dc.contributor.advisorGoodwin, Douglasen_US
dc.contributor.advisorGorden, Anne E. V.en_US
dc.contributor.authorLi, Weikuanen_US
dc.date.accessioned2009-02-23T15:56:21Z
dc.date.available2009-02-23T15:56:21Z
dc.date.issued2008-08-15en_US
dc.identifier.urihttp://hdl.handle.net/10415/1540
dc.description.abstractAristeromycin and neplanocin A are two examples of potent S-adenosylhomocysteine hydrolase inhibitors. As a consequence, they show significant broad-spectrum antiviral activity, however, their clinical potential is limited by toxicity, which is associated with phosphorylation at their 5'-hydroxyl groups. 5'-Noraristeromycin has been found to exhibit wide-spectrum antiviral activity with reduced toxicity due to its inability to form the corresponding nucleotide. To explore new antiviral agents retaining aristeromycin-based activity while reducing undesired toxicity, 5'-fluoro-5'-deoxyaristeromycin (1), 4'-fluoro-4'-deoxynoraristeromycin (2), 3,7-dideazaaristeromycin (3) and 3,7-dideazanoraristeromycin (4) were synthesized. Compounds 1 and 2 showed moderate activity against measles but were inactive in other antiviral assays. Compounds 3 and 4 exhibited no significant activity against all viruses tested. Another member of the adenosine (Ado) set is sinefungin (5), which is a naturally occurring analog of S-adenosyl-L-homocysteine (AdoHcy) or S-adenosylmethionine (AdoMet). The wide-spectrum biological activities (anti-fungal, anti-virus, anti-bacteria and anti-malarial) are associated with its inhibition of AdoMet dependent methyltransferases. The application of sinefungin is limited by its toxicity. A convenient synthesis of sinefungin and related compounds (6, 7 and 8) was developed.en_US
dc.language.isoen_USen_US
dc.rightsEMBARGO_NOT_AUBURNen_US
dc.subjectChemistry and Biochemistryen_US
dc.titleSeeking MRNA Methylation Inhibitors as Antiviral Agentsen_US
dc.typeDissertationen_US
dc.embargo.lengthMONTHS_WITHHELD:6en_US
dc.embargo.statusEMBARGOEDen_US
dc.embargo.enddate2009-08-23en_US

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