Peptide compounds

Details Peptide compounds Peptide compounds

1995-03-13

1999-03-16

Housel, James C.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

4242781, 530334, 530345, A61K 39385, A61K 3800

Patent

active

058826459

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to peptide compounds which comprise a lipophilic anchor section formed from at least one fatty amino acid moiety and a matrix core section having at least four amino acid functionalities which are the same and are selected from --NH.sub.2, --COOH, --SH, --OH and derivatives thereof. Pharmaceutically active moieties, especially peptide antigens, can be bound to the amino acid functionalities for use as, for instance, vaccines and diagnostic agents. The lipophilic anchor allows the compound to be incorporated into lipid vesicles and/or cell membranes. The invention includes a process for producing the new compound by conventional peptide synthesis, usually on a solid matrix.
It is well recognised that synthetic peptides can induce antibodies reactive with their cognate sequences in the native proteins, that is the synthetic peptide and native protein comprise the same epitope. Specific antibodies are useful as reagents in various investigations. Furthermore peptide antigens, made by available peptide synthesis techniques, are useful for producing immunogens and for immunoprophylaxis and in affinity purification of proteins, antibodies, or other molecules.
Small peptide molecules may not be of sufficient molecular weight themselves to be immunogenic at all or to a sufficient degree, but can be rendered immunogenic or more immunogenic by conjugation to a carrier molecule, for instance to a protein or a synthetic polymer. The use of proteins, for instance bovine serum albumin (BSA), has been described. Although the conjugated product is antigenic, it comprises a large number of epitopes other than that associated with the synthetic peptide of interest. Di Marchi et al in Science (1986) 232, 639-641 describe a synthetic peptide comprising two immunologically significant regions of a virus coat protein joined by a spacer which has adequate molecular weight to induce an immune response. Again the spacer region can act as an epitope, which is undesirable.
James P Tam, in Proc. Natl. Acad. Sci. USA (1988) 85, 5409-5413, describes a new approach to increasing the molecular weight of synthetic peptide antigens called the multiple antigen peptide system (MAP). The MAP comprises a core matrix formed of a low number (n) of sequential levels of dendritically joined trifunctional amino acids, in practice lysine molecules. The core matrix has 2.sup.n terminal functionalities, in practice amine functionalities, each of which can be conjugated with a synthetic peptide. The MAP was synthesized by forming the core matrix using conventional step wise solid phase procedure by contacting an excess of symmetrical anhydride of N.sup..alpha., N.sup..epsilon. -Boc-Lys(Boc) with (Boc)-.beta.-Ala-OCH.sub.2 -Pam resin (phenyl-acetamido methyl resin). Subsequent levels of the core were formed by similar steps. To each terminal amine functionality, a preformed synthetic peptide antigen molecule was joined via triglycyl linker, followed by cleavage from the resin by known means. In a MAP in which the matrix core comprises three levels of lysine and thus 2.sup.3 amine groups, there will be 8 peptide groups per molecule, and where the peptide antigen groups each have a molecular weight of say 1200 the peptide antigen accounts for more than 80% of the total weight of the MAP. The MAP was antigenic, raising antibodies reactive with native proteins including the same peptide sequence (p60.sub.src)
4-branch and 8-branch versions of F-moc protected dendritically-linked poly-lysine cores attached to peptide synthesis resins via a .beta.-alanine residue are commercially available from Applied Biosystems, Inc.
At the 12th American Peptide Symposium in Boston in 1991, Defoort et al, describe a MAP with a preformed lipid anchor conjugated to it to allow incorporation into liposomes. The lipid anchor comprises a total of 3 hydrophobic chains per molecule. The lipid tails comprise fatty acids (palmitoyl groups) joined by esterification reactions to the two free hydroxyl groups of glycerol, acting as a polyhydroxy linker comp

REFERENCES:
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Tam, J.P., "Synthetic Peptide Vaccine Design: Synthesis and Properties of a High-Density Multiple . . . ", Proc. Natl. Acad. Sci. USA, vol. 85, Aug. 1988, pp. 5409-5413.
Tam, J.P., et al., "Mechanisms for the Removal of Benzyl Protecting Groups in Synthetic Peptides by Trifluoromethanelsulfonic Acid-Trifluoroacetic Acid-Dimethyl Sulfide", J. Am. Chem. Soc., 1986, vol. 108, pp. 5242-5251.
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Toth, I., et al., "Lipidic Peptides X.sup.1. Synthesis, Structural and Physico-Chemical Elucidation of Lipidic Amino Acid Conjugates With Hydrophilic Compounds", Tetrahedron, vol. 48, No. 5, 1992, pp. 923-930.
Defoort, J-P., et al., "Complete Synthetic Vaccine With Built-In Adjuvant", Rockefeller University, pp. 845-846. Chem. Biol., Proc. Am Pept. Symp. 12th (1991).
DiMarchi, R., et al., "Protection of Cattle Against Foot-and-Mouth Disease by a Synthetic Peptide", Science, vol. 232, May 2, 1986, pp. 639-641.
Toth, I., et al., "Lipidic Amino Acid Based Synthetic Peptide Vaccine Adjuvant", Immunological Satellite Meeting, Budapest, Aug. 29-31, 1992 Abstract Only.
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Defoort, J-P., et al., "Macromolecular Assemblage in the Design of a Synthetic AIDS Vaccine", Proc. Natl. Acad. Sci. USA, vol. 89, May 1992, pp. 3879-3883.

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