The infectious agents causing scrapie and other transmissible spongiform encephalopathies have been postulated to consist solely of the protease-resistant form of prion protein (PrPSc). One unprecedented requirement of the protein-only model is that the 'inheritance' of pathogen strain differences must be mediated by stable variations in PrPSc structure, rather than mutations in an agent-specific nucleic acid. Strain differences in PrPSc structure have been described for the hyper (HY) and drowsy (DY) strains of hamster transmissible mink encephalopathy (TME), a scrapie-like disease originating in mink. Although HY and DY PrPSc are both post-translationally derived from the precursor prion protein (PrPC) they are cleaved at different amino-terminal sites by proteinase K (ref. 8). Here we investigate whether this strain-specific property of PrPSc is transmitted to PrPC during formation of new PrPSc. PrPSc from the HY and DY TME strains converted the protease-sensitive PrPC into two distinct sets of protease-resistant PrP products in a cell-free system. These data provide evidence that self-propagation of PrPSc polymers with distinct three-dimensional structures could be the molecular basis of scrapie strains.

The structure of capuramycin ( 1) is confirmed by an efficient synthesis that features glycosylation with a D-monno-pyranuronate donor 15 at the hindered C-5' hydroxyl of L-to/o-uridine 10.Capuramycin (1) is a complex nucleoside antibiotic* 1 produced by Streptomycesgriseus 446-S3 in culture broth.

The liposidomycins comprise a family of complex nucleoside antibiotics that inhibit bacterial peptidoglycan synthesis. Their structures (1, 2) feature nucleoside, ribofuranoside, diazepanone, and lipid regions. Several stereogenic centers remain unassigned, including three within the diazepanone region: C-6', C-2'", and C-3'". An intramolecular reductive amination reaction has been used to prepare model diazepanones. Analysis of 40 and two of its diastereomers by NMR spectroscopy, X-ray crystallography, and molecular modeling indicates a close relative configurational and conformational match between 40 and the liposidomycin diazepanone degradation product 43 and allows the assignment of stereochemistry of the natural products as either [C-6'(R), C-2'"(R), C-3'"(R)] or [C-6'(S), C-2'"(S), C-3'"(S)].

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