Peptide compounds

• US 5,882,645 A
• Filed: 03/13/1995
• Issued: 03/16/1999
• Est. Priority Date: 07/24/1992
• Status: Expired due to Term

• Current Assignee: The University Of London School Of Pharmacty
• Original Assignee: The School Of Pharmacy, University Of London
• Inventors: Toth, Istvan, Gibbons, William Anthony
• Primary Examiner(s): Housel, James C.
• Assistant Examiner(s): ASHTON, ROSEMARY E
• Application Number:
  US08/374,560
• Time in Patent Office: 1,464 Days
• Field of Search: 424/194.1, 424/193.1, 424/278.1, 530/345, 530/334
• US Class Current: 424/194.1
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/646 the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C07K 14/295 from Chlamydiales (O)
• CPC Class Codes: C07K 2319/40 containing a tag for immunodetection, or an epitope for immunisation
• CPC Class Codes: C12N 2770/32122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Abstract

Synthetic peptides are widely used to generate antibodies. To induce high antibody response, it is known to conjugate the peptide to a carrier protein (e.g. KLH, BSA) or to incorporate it into polylysine to form a multiple antigenic peptide. Anchors may be built in which are based on fatty acids. According to the invention there is provided a novel lipidic amino acid based anchor system which can maximally enhance the antigenicity of a short synthetic peptide. These novel compounds are entirely peptide-based and may therefore be produced automatically by some step wise peptide synthesis, preferably solid phase step wise peptide synthesis. According to the invention there is also provided such a process.

Claims

1. A peptide compound comprising at least 2 amino acid moieties joined together by peptide bonds, the compound comprising a lipophilic anchor which is connected to an amino acid moiety of the compound by a peptide bond and which comprises at least two amino acid moieties directly joined to one another by peptide bonds, each amino acid moiety being of the formula I ##STR4## wherein each R¹ is independently a linear or branched chain alkyl or alkenyl group having 6-24 carbon atoms, the compound comprising also a matrix core section comprising n levels of dendritically linked trifunctional amino acid moieties, in which n is an integer of 2 or more, the or each trifunctional amino acid moieties comprising either two carboxylic acid groups or two amine groups and the matrix core having at least two terminal functionalities which are selected from --NH₂, --COOH, --OH, --SH and derivatives thereof.

2. A peptide compound according to claim 1, wherein n is 2, 3 or 4.

3. A peptide compound according to claim 1 wherein the lipophilic anchor section is joined to the central amino acid of the matrix core section, directly or via a linker group.

4. A compound comprising a peptide compound according to claim 1, in which a pharmaceutically active substituent is joined to each of the terminal functionalities.

5. A compound according to claim 4, wherein all of the pharmaceutically active substituents are the same.

6. A compound according to claim 4, wherein each pharmaceutically active substituent is joined to the peptide compound by a peptide bond.

7. A composition comprising a compound according to claim 4 and a pharmaceutically active carrier.

8. A composition according to claim 7, wherein the compound comprises a peptide antigen capable of eliciting an immune response.

9. A liposome composition comprising a compound according to claim 1 anchored in a lipid vesicle via the lipophilic anchor section.

10. A liposome composition according to claim 9, wherein the compound comprises a peptide antigen capable of eliciting an immune response.

11. A compound according to claim 1 additionally comprising a resin support linked directly via a peptide bond or indirectly via a linker peptide moiety to the lipophilic anchor section.

12. A compound according to claim 1 having the formula ##STR5## wherein Z, Z¹ and Z² are independently selected from a bond, an amino-acid residue and an oligopeptide residue, R³ and R⁴ are independently selected from H, an amine protecting group, a pharmaceutically active moiety, and a group III ##STR6## wherein R^3'"'"', R^4'"'"', Z^1'"'"' and Z^2'"'"' are selected from the same groups represented by R³, R^4'"'"' Z¹ and Z², respectively,

p is 0 or an integer,

the or each R² is independently selected from linear and branched chain alkyl and alkenyl groups having 6 to 24 carbon atoms and naturally-occurring amino acid side chains,

q is an integer of at least 1

the or each R¹ is independently selected from linear and branched chain alkyl and alkenyl groups having 6 to 24 carbon atoms,

Y is OH, NH₂, a carboxylic acid protecting group or comprises an amino acid or oligopeptide moiety a resin on which the peptide has been synthesised.

13. A process of producing a peptide compound comprising a lipophilic anchor which is connected to an amino acid moiety of the compound by a peptide bond and which comprises at least two amino acid moieties directly Joined to one another by peptide bonds, each amino acid moiety being of the formula I ##STR7## wherein each R¹ is independently a linear or branched chain alkyl or alkenyl group having 6-24 carbon atoms, the compound comprising also a matrix core section comprising n levels of dendritically linked trifunctional amino acid moieties, in which n is an integer of 2 or more, the or each trifunctional amino acid moieties comprising either two carboxylic acid groups or two amine groups and the matrix core having at least two terminal functionalities which are selected from --NH₂, --COOH, --OH, --SH and derivatives thereof,

said process comprising reacting of the amine or carboxylic acid equivalent of the lipophilic anchor with the carboxylic acid or amine equivalent, respectively, of said amino acid moiety of the compound to form said peptide bond.

14. A process according to claim 13, wherein the formation of said peptide compound is carried out as a solid phase peptide synthesis step in which the forming peptide compound is attached to a resin.

15. A process according to claim 14, wherein the process comprises the formation of peptide bonds between the moieties of formula I and of peptide bonds between the amino acid moieties of the matrix core section, sequentially and without cleavage of the forming peptide compound from the resin.

16. A process according to claim 15, wherein the peptide compound is a compound joined to each of the terminal functionalities by a peptide bond and wherein each terminal functionality is amine or carboxylic acid group or derivative thereof and wherein each peptide bond which joins a pharmaceutically active substituent to a terminal functionality is formed by reacting the amine or carboxylic acid moiety or derivative thereof of said pharmaceutically-active substituent with said terminal functionality whilst the forming peptide compound is attached to the resin.