Peptide compounds which inhibit the proliferation of epidermal o

Details Peptide compounds which inhibit the proliferation of epidermal o Peptide compounds which inhibit the proliferation of epidermal o

1991-04-08

1996-01-16

Warden, Jill

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530329, 530330, 514 16, A61K 3800, C07K 500, C07K 700, C07K 1700

Patent

active

054847702

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of peptides having an inhibitory effect on cell proliferation, and to novel peptides having specific and/or general inhibitory effects.
The mammalian body contains cells having enormously diverse structures and functions, and the mechanisms of differentiation and development have been the focus of much study. It is known that for systems of cells having a continuous turnover the mechanism commonly involves a reservoir of pluripotent stem cells which divide and constantly supply new cells to the system. While initially homogeneous the stem cells supplied from the "reservoir" soon become committed to one or other morphology and subsequently develop into the required functional cells.
Examples of such stem cell systems are the haemopoietic system in bone marrow and the epithelial and epidermal systems.
It has previously been reported that peptides corresponding to a narrow general formula can inhibit haemopoiesis (see EP-A-0112656), while a group of dimeric peptides corresponding to a slightly broader general formula and linked by a disulphide bridge could stimulate haemopoiesis (see WO88/03535). It was stated in both cases, however, that no effects were observed on systems other than haemopoiesis.
We have now surprisingly found that a class of peptides, including certain of the peptides disclosed in EP-A-0112656, have a more general ability to inhibit cell proliferation, and that minor modifications to the amino-acid sequence and/or blocking of critical side-chain residues can direct the action of the peptides to specific systems of interest.
Our findings have been based on the observation that certain of the pentapeptide sequences disclosed in our above patent applications occurred in certain so-called G-proteins, namely G.sub..alpha.i proteins. The G proteins are found on the interior side of cell membranes and provide an essential link between transmembrane receptors and effectors located near the G proteins inside the cell. They are involved in many cell functions, according to the effectors with which they are linked. They consist of 3 linked sub-units .alpha., .beta. and .gamma., the .alpha. sub-unit being involved in activating the adjacent effector. The G proteins were initially characterised by their function and the sub-class of G.sub.i proteins are those originally found to inhibit adenylate cyclase. This finding led to the consideration of the role of the peptides in inhibition of proliferation of the epithelial and epidermal systems and cell systems generally.
Thus according to the invention we provide the use of compounds of formula (I) ##STR1## R.sup.b represents ##STR2## R.sup.c represents ##STR3## R.sup.d represents ##STR4## R.sup.e represents ##STR5## and R.sup.f represents ##STR6## (wherein n and m independently represent 0 or 1; group; carbon--carbon bond; group, group, which may carry one or more hydroxy, amino or methoxy substituents; or a metabolically labile S-protecting group; glutamine or a peptide having an N-terminal glutamine unit; the said amino acid residues are in the L-form) in the preparation of a medicament for the inhibition of non-haemopoietic cell proliferation.
Where an N-terminal protecting group R.sup.5 is present this may, as indicated above, be an acyl group having 1-20 carbon atoms, e.g. a lower alkanoyl group having 1-5 carbon atoms such as the acetyl group, or an aroyl or aralkanoyl group having 7 to 20 carbon atoms such as the benzoyl or phenylacetyl group.
R.sup.5 may also be an acyl group derived from an amino acid or a peptide chain. In particular, R.sup.5 may be an acyl group derived from serine or any of the peptides derived from the following amino acid sequence by removal of successive N-terminal amino acids: Lys-Ile-Ile-His-Glu-Asp-Gly-Tyr-Ser.
As explained in detail hereinafter, peptides having the above sequence or part thereof have a high level of homology with G.sub.i.alpha. proteins which are known to control a number of cell functions including inhibition of growth. The terminal amino group of the overall pe

REFERENCES:
Fong et al., Proc. Natl. Acad. Sci., vol. 85, May 1988, pp. 3066-3070.
Laerum et al., Chemical Abstracts, vol. 109, Abst No. 36328w 1988.
Kreja et al., Chem Abstr., vol. 105, p. 127, Ab No. 203843m 1986.
Laerum et al., Chem Abstr., vol. 103, Abst No. 194825m 1985.
Foa et al., Chem Abstr., vol. 106, Abst. No. 96321m, 1987.
Bodanszky, Int. J. Peptide Protein Research, vol. 25, pp. 449-474, 1985.
Gilman, Annual Review of Biochemistry, 56, 610-645, 1987.
Neer, et al., Nature, 333, 129-134, 1988.
Snyderman, et al., Journal of Leukocyte Biology, 40, 785-800, 1986.
Didsbury, et al., FEBS Letters, 219, 259-263, 1987.
Levitsky, TIBS, 13, 298-301, 1988.

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