Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1996-09-27
1998-03-31
Tsang, Cecilia
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
435 711, 43525235, 514 9, C07K 706, C12P 2102, C12R 1465
Patent
active
057340137
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a microorganism strain and to novel peptides which display farnesyl transferase inhibitory properties.
Activation of ras oncogenes is implicated in 10 to 30% of human cancers. The corresponding Ras protein is synthesized in vivo in the form of a cytosoluble precursor which is then modified post-translationally so as to confer on it its biological activity and to enable it to transform mammalian cells.
The first and obligatory step in these post-translational modifications consists of a farnesylation of the thiol group of a cysteine residue which is located in the carbonyl terminal group of Ras. This cysteine residue is part of the prenylation identification sequence CAAX, where C represents cysteine, A represents an aliphatic residue and X represents any amino acid.
The protein farnesyl transferase catalyses the transfer of a farnesyl group from farnesyl diphosphate to the Ras CAAX peptide. This farnesyl transferase protein recognizes tetrapeptides of the CAAX type which are located at the C-terminal end of the protein under the express stipulation that the fourth residue from the C-terminal end is a cysteine.
At the conclusion of this prenylation, the Ras protein possesses the biological activity which is required for transforming cells. The prenylation therefore appears to be necessary for regulating the biological activity of the Ras protein.
The discovery of compounds which inhibit its post-translational modification was rapidly seen to be a means for developing novel anti-cancer treatments.
Thus, genetic studies demonstrated that inhibition of the farnesylation of Ras prevented the Ras protein from locating in the membrane and consequently blocked its ability to transform normal cells into cancerous cells.
The principal object of the present invention is to propose novel inhibitors of farnesyl transferase.
More precisely, the present invention results from the isolation of a microorganism strain which belongs to the Streptomyces genus and which possesses properties which are particularly advantageous for producing peptides which display inhibitory properties with regard to the protein farnesyl transferase.
One aspect of the invention therefore relates to a Streptomyces strain which is characterized in that it is the microorganism Streptomyces CBS 154.94, one of its derivatives or one of its mutants.
Within the meaning of the present invention, derivative or mutant is understood to mean any strain which is obtained from the strain Streptomyces CBS 154.94 and which can be used for producing peptides which are in accordance with the invention and which, more particularly, display inhibitory properties with regard to the protein farnesyl transferase. In particular, such derivatives or mutants can be obtained by means of genetic (alteration of the DNA) or biochemical modifications. Different mutagenesis aids can be used for this purpose, such as, for example, non-specific aids: etc.), (transposons, retrotransposons, integrating plasmids, etc.).
Fermentation of this strain on a suitable culture medium and subsequent extraction of the corresponding fermentation broth enables peptides to be isolated which, although possessing a structure which is novel as compared with that of the conventional inhibitors of farnesyl transferase, are unexpectedly found to be of interest in this regard.
The present invention also relates to peptides which can be obtained by fermenting the Streptomyces CBS 154.94 strain, or one of its mutants, and extracting the corresponding fermentation broth.
The present invention also relates to a process for producing peptides according to which the strain Streptomyces CBS 154.94, or one of its derivatives or mutants, is cultured and at least one peptide is recovered.
The strain is fermented in a conventional manner, namely on a culture medium containing the substrates which are necessary for the development of the said microorganism and under appropriate temperature and aeration conditions. It is evident that determination of these conditions which are opti
REFERENCES:
Hancock, Anti-Ras drugs come of age. Current Biology, 3(11), 770-772 1993.
Hara et al. Identification of Ras farnesyltransferase inhibitors by microbal screening. Proc. Natl. Acad. Sci. USA, 90, 2281-2285 1993.
Internal Medicine, 4th Edition, Editor-In-Chief Jay Stein, Chapters 71-72, pp. 699-715 1992.
Journal of Antibiotics, vol. 46, No. 2, pp. 222-228, Feb., 1993 Omura Van Der Pyl Inokoshi Takahashi Takeshima Pepticinnamins, New Farnesyl-Protein Transferase Inhibitors Produced by an Actinomycete.
Journal of Antibiotics, vol. 46, No. 2, (pp. 229-234), Feb., 1993 Shiomi Yang Inokoshi Van Der Pyl Nakagawa Takeshima et al. Pepticinnamins, New Farnesly-Protein Transferase Inhibitors Produced by an Actinomycete.
Debernard Jean-Jacques
Flamant Thierry
Van Der Pyl Didier
Bozin Michael
Martin Michael B.
Parker III Raymond S.
Rhone-Poulenc Rorer S.A.
Smith Julie K.
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