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AssigneeGovernment of the U.S. of America, Secretary of the Department of Health and Human Services
InventorsBruce W. Chesebro, Byron W. Caughey, Joelle Chabry, Suzette Priola
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Peptides are disclosed that inhibit the conversion of protease sensitive prion protein (PrPsen) to the protease resistant isoform (PrPres). These peptides comprise discrete fragments of prion proteins, and are shown to inhibit the in vitro conversion of PrPsen to PrPres in a cell-free system. Numerous peptides are disclosed that include at least two amino acid residues from the highly amyloidogenic region P113-120 of the PrP protein. None of these peptides conferred protease-resistance to the PrPsen molecules. The presence of residues 119 and 120 from the highly hydrophobic sequence AGAAAAGA (position 113 to 120) produced a particular inhibitory effect. The inhibition occurred with a high degree of specificity (e.g. with an IC50 of less than about 1000 μM).
A purified peptide consisting essentially of XZ, where X is at least two consecutive amino acid residues from the amino acid sequence Ala Gly Ala Ala Ala Ala Gly Ala (SEQ. ID. NO.1), or a variant thereof, and Z is a peptide region of the PrP protein, or a variant thereof that, in cooperation with X, inhibits conversion of protease sensitive prion protein (PrPsen) to protease resistant prion protein (PrPres).
A purified peptide consisting essentially of SEQ. ID. NO. 6.
A purified peptide XZ, where X consists of two consecutive carboxy terminal amino acids of SEQ. ID. NO. 1, and Z comprises at least the first eight consecutive amino acids of SEQ. ID. NO. 13 or 24.
A purified peptide consisting of the amino acid sequence of SEQ. ID. NO. 9.
A purified peptide which:
A composition comprising a peptide XZ, where X is at least two consecutive amino acid residues from the amino acid sequence Ala Gly Ala Ala Ala Ala Gly Ala (SEQ. ID. NO. 1), and Z is a peptide region of the PrP protein, or a variant thereof that, in cooperation with X, specifically inhibits conversion of protease sensitive prion protein (PrPsen) to protease resistant prion protein (PrPres).
A synthetic peptide homologous to at least a portion of SEQ. ID. NO. 1, and which specifically functionally disrupts formation of PrPres from PrPsen under conditions in which a conversion from PrPsen to PrPres would otherwise be expected to occur.
A method of screening for compounds which functionally disrupt formation of PrPres, comprising:
A method of treating a mammal having a spongiform encephalopathy in which PrPsen is converted to PrPres, comprising administering to the mammal a pharmacologically effective amount of a drug comprising a peptide comprising SEQ. ID. NO. 6, or a variant peptide, analog or mimetic thereof, to interfere with PrPres formation, or to destabilize PrPres protein structures already formed in the mammal.
A method of treating a mammal having a condition associated with formation of PrPres, comprising:
A pharmaceutical composition, comprising a purified peptide consisting essentially of SEQ. ID. NOS. 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16 , 17 or 23.
A purified peptide comprising SEQ. ID. NO. 6, but not positions 90-100 of SEQ. ID. NOS. 19 or 20.
Dependencies are inferred from the claim text.