Effects of new amphotericin analogues on the scrapie isoform of the prion protein.
Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of neurodegenerative disorders associated with the conversion of a normal host prion protein (PrP(C)) into a pathogenic isoform (PrP(Sc)). Despite years of research, there is still no known cure for TSEs. Amphotericin B (AmB), an anti-fungal antibiotic, has antiprion activity but its usage is limited by its toxicity. This study assessed the antiprion properties of new amphotericin analogues in which the exocyclic carboxyl groups were replaced by methyl groups. These analogues reduced levels of the abnormal PrP(Sc) isoform of the mouse prion protein in cultured cells. 16-descarboxyl-16-methyl-amphotericin B (16B) had antiprion activity equivalent to that of amphotericin B and was significantly less toxic to cells as determined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide dye reduction assay. A non-anti-fungal analogue, 16-descarboxyl-16-methyl-19-O-(6-deoxyhexosyl)-19-O-desmycosaminyl-amphotericin (16-19B) had higher antiprion activity and significantly lower toxicity than AmB. Some of the new amphotericin analogues may have potential as antiprion drugs.
Soler
Lara
L
Prion Research group, Ardmore House, UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Caffrey
Patrick
P
McMahon
Hilary E M
HE
D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020128:Inhibitory Concentration 50; D051379:Mice; D011090:Polyenes / Q000494:pharmacology; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism
D000975:Antioxidants; D011090:Polyenes; D018620:PrPSc Proteins; D020033:Protein Isoforms; D000666:Amphotericin B; D002374:Catalase; D001205:Ascorbic Acid