Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 25 or more amino acid residues in defined sequence
Patent
1994-06-02
1998-06-30
Knode, Marian C.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
25 or more amino acid residues in defined sequence
530323, 530326, 530334, 536 235, C07K 14435, C07H 2104
Patent
active
057735727
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/02246, filed Dec. 3, 1992.
The present invention relates to synthetic polypeptides. In particular it relates to synthetic polypeptides which emulate the three-dimensional structures and/or electrostatic surfaces and/or other physical, chemical and structural properties of specific regions of proteins thought to be the involved in the molecular pathology of spongiform encephalopathies. It is of particular interest to the design of immunodiagnostics, vaccines and other medical, veterinary or scientific agents in relation to human, bovine and ovine spongiform encephalopathies.
Spongiform encephalopathies are a group of degenerative neurological diseases. Examples have been found in a number of species including sheep (where it is known as scrapie), cows (BSE) and humans (Creutzfeldt-Jakob disease (CJD) and kuru) (Review article, Taylor, D. M. Veterinary Record 125, 413-415 (1989)). Similar conditions have also been found in the wild mink population and in captive kudus (a kind of antelope) and tigers. It has been variously reported that BSE can be transmitted under laboratory conditions to mice and pigs. This crossing of species barriers by the infective agent has led to increased concern that transfer to humans could occur.
These diseases are characterised by a slow incubation time of four to five years after which the clinical symptoms of progressive degeneration of mental state, including aggressiveness and lack of coordination, appear. Post mortems reveal a characteristic pattern of vacuolation in brain tissue due to the destruction of neural cells, and the deposition of unusual protein fibres.
Although the form of the disease found in sheep (scrapie) has been known for many years, spongiform encephalopathies have come to prominence within the last decade following the appearance of BSE in cattle farms. The incidence of BSE in the United Kingdom has increased markedly during this period and public concern over the possible transmission of the disease to humans has led to a collapse in the beef market. Thus for both veterinary and economic reasons, there is an urgent need for diagnostic agents to detect infection and for vaccines to prevent infection.
It is believed that the causative agent of scrapie and its counterparts in other animals is a so-called "prion", that is an infective particle comprising protein only and no nucleic acid, the presence of the latter being required in the case of a conventional virus. In scrapie, one particular protein (termed prion protein, PrP.sup.SC) has been found to co-purify with infectivity and can produce a scrapie-like condition in brain cell cultures from other animals, such as hamsters, under laboratory conditions. PrP.sup.SC is the only known component of the characteristic protein fibres deposited in the brain tissue of scrapie-infected sheep. The term "PrP.sup.SC " as used herein should be taken to refer not only to the specific Prion protein identified in sheep but also to those homologous proteins found in many other species which appear to undergo a structural modification as described hereinafter. The term "PrP.sup.C " shall be used in respect of the normal cellular counterpart to PrP.sup.SC.
The major problem in the search for a specific diagnostic agent or synthetic vaccine against the scrapie agent PrP.sup.SC is that it is almost identical to the natural form of the protein PrP.sup.C. The natural function of this protein is not yet understood but the remarkably strong conservation of primary structure between homologous proteins from different species suggests that it has an essential structural or functional role within the organism.
In spite of the almost identical form of these prions to the natural proteins, we have deduced synthetic peptide structures comprising at least one antigenic property, such as an epitopic site and these synthetic peptides may be used to produce diagnostic agents and vaccines.
The responses of the B and T cells of the immune system are not specified by a global recognition of a whole protei
REFERENCES:
Cell, vol. 46, 417-428, Aug. 1986, "Scrapie and Cellular PrP Isoforms Are Encoded by the Same Chromosomal Gene", by K. Besler et al.
Proc. Natl. Acad. Sci., USA, vol. 87, pp. 2476-2480, Apr. 1990, "Two alleles of a neural protein gene linked to scrapie in sheep", by W. Goldman et al.
Journal of Molecular Recognition, vol. 4, 85-91, 1991, "Production and Characterization of Antibodies to Mouse Scrapie-Amyloid Protein Elicited by Non-carrier Linked Synthetic Peptide Immunogens", by Alessandro Di Martino et al.
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Neurology, 1990, 40:513-517, "Scrapie-associated precursor proteins: Antigenic relationship between species and immunocytochemical localization in normal, scrapie, and Creutzfeldt-Jakob disease brains" by J. Safar, MD et al.
The Journal of Immunology, vol. 140 1188-1193, No. Feb. 1988, "Characterization of Prion Proteins with Monospecific Antisera to Synthetic Peptides", by R. Barry et al.
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Journal of Virology, vol.62, No. 5, May 1988, pp. 1558-1564, "Scrapie-Infected Murine Neuroblastoma Cells Produce Protease-Resistant Prion Proteins",by D. Butler.
Laboratory Investigation, vol. 57, No. 6, p.646, 1987, "Immuno-Gold Localization of Prion Filaments in Scrapie-Infected Hamster Brains", by Clayton A. Wiley et al.
J. gen Virol. 1986, 67, 1745-1750, "Immunoreactivity of a Synthetic Pentadecapeptide Corresponding to the N-Terminal Region of the Scrapie Prion Protein", by M. Shinagawa et al.
Cell, vol. 38, 127-134, 1984, "Purification and Structural Studies of a Major Scrapie Prion Protein" by Stanley Prusiner et al.
The Journal of immunology, vol. 147, 3568-3574, No. 10, Sep. 1991, "Epitope Mapping of the Syrian Hamster Prion Protein Utilizing Chimeric and Mutant Genes in a Vaccinia Virus Expression System", Mark Rogers et al.
Fishleigh Robert Vincent
Mee Roger Paul
Robson Barry
Knode Marian C.
Proteus Molecular Design Limited
Wortman Donna C.
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