2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPSc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.
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October 2002
Our discovery of dominant-negative inhibition of prion formation in cultured cells provided an explanation for the resistance of some sheep to scrapie and humans to Creutzfeldt-Jakob disease. To determine whether dominant-negative inhibition occurs in vivo, we produced transgenic (Tg) mice expressing prion protein (PrP) with either the Q167R or Q218K mutation alone or in combination with wild-type (wt) PrP. Tg(MoPrP,Q167R)Prnp(0/0) mice expressing mutant PrP at levels equal to non-Tg mice remained healthy for >550 days, indicating that inoculation with prions did not cause disease.
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