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Small Peptides And Methods For Inhibiting The Migration Of T-Cells

a technology of t-cells and small peptides, which is applied in the direction of peptide/protein ingredients, extracellular fluid disorders, immunological disorders, etc., can solve the problems of affecting the inflammatory response of the immune system, affecting the inflammatory response, so as to prevent the involvement of the immune system in the increased inflammatory respons

Inactive Publication Date: 2008-09-04
HOUCK JOHN C +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides methods for treating various indications using a peptide called f-Met-Leu-X, which has mast cell degranulation inhibition activity. These methods include treating allergies, cutaneous inflammation, arthritis, and chronic obstructive pulmonary disease. The peptide can also be used to replace corticosteroids in applications where immunosuppression is needed. The invention also provides methods for inhibiting the infiltration of eosinophils into airways and inhibiting mucous release in airways. The peptide can also block the activation of lymphocytes and is useful for blocking IgE activation of monocytes, eosinophils, and TNF."

Problems solved by technology

T cells and mast cells release cytokines that promote eosinophil growth and maturation and the production of IgE antibodies, and these, in turn, increase microvascular permeability, disrupt the epithelium, and stimulate neural reflexes and mucus-secreting glands.
The result is airways hyperreactivity, bronchoconstriction, and hypersecretion, manifested by wheezing, coughing, and dyspnea.
These agents help the symptoms of asthma, but do nothing for the underlying inflammation.

Method used

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  • Small Peptides And Methods For Inhibiting The Migration Of T-Cells
  • Small Peptides And Methods For Inhibiting The Migration Of T-Cells
  • Small Peptides And Methods For Inhibiting The Migration Of T-Cells

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0070]A dose response curve was prepared for the standard compound, f-Met-Leu-Phe, using the selected dose of 0.15 μg Compound 48 / 80. Doses of 0 to about 230 nM of f-Met-Leu-Phe were tested and the results are shown in FIG. 2. Inhibition of degranulation induced by Compound 48 / 80 was clearly shown.

examples 2-11

[0071]Several f-Met-Leu peptides were tested for inhibition of induced degranulation in the rat skin model using 100 nanomoles of the test peptide and a dose of 0.15 μg Compound 48 / 80. An intrinsic zero-peptide-dose 48 / 80 control was included in each rat for each experiment, and the % of inhibition was expressed in relative terms to this control (0% inhibition). The percent mast cell degranulation produced by 48 / 80 was also determined. The results are tabulated below.

TABLE 1SEQ%%ExamplePeptideIDInhibitionDegranulation*2f-Met-Leu-Phe (prior art)30603N-acetyl-Met-Leu-Phe0984N-t-BOC-Met-Leu-Phe0—5f-Met-Leu-(iodo)Phe0—6f-Met-Leu-Phe(benzylamide)0—7f-Met-Leu-Phe-Lys40—8f-Met-Leu-Phe(methyl ester)0—9f-Met-Leu-Phe-Phe21001-310f-Met-Leu-Tyr553011f-Met-Leu-Tyr-Tyr50—

example 12

[0072]A dose response curve was prepared for f-Met-Leu-Phe-Phe using the selected dose of 0.15 μg Compound 48 / 80. Doses of 0 to about 230 nM of f-Met-Leu-Phe-Phe were tested and the results are shown in FIG. 3. Surprisingly remarkable inhibition of degranulation induced by Compound 48 / 80 was clearly shown. The inhibition of induced degranulation for f-Met-Leu-Phe-Phe was unexpectedly substantially better than that of the standard compound f-Met-Leu-Phe.

The OVA-induced Bronchial Asthma Mouse Model for Inhibition of Mast Cell Degranulation

[0073]Asthma is a complex disease, which is characterized by spontaneous exacerbation of airways obstruction and persistent bronchial hyperresponsiveness. Chronic infiltration with activated T-lymphocytes, eosinophils and macrophages / monocytes of the airway submucosa is another established feature. Inflammatory mechanisms, with expression of cytokines, and the release of inflammatory mediators, underlie the pathogenesis of bronchoconstriction and bro...

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Abstract

Methods for treating cutaneous inflammation, are described. Also described is a method for inhibiting the mucous release into airways of a patient, a method for blocking IgE activation of a lymphocyte, a method for stabilizing the cell membrane of a lymphocyte, thereby preventing their further involvement in the increased inflammatory response to an IgE antigen challenge, and a method for inhibiting the migration of T-cells. Such methods involve administering to said patient a therapeutically effective amount of a peptide having the formula f-Met-Leu-X, wherein X is selected from the group consisting of Tyr, Tyr-Phe, Phe-Phe and Phe-Tyr.

Description

RELATED APPLICATIONS[0001]This application is a Division of U.S. application Ser. No. 10 / 147,633 filed May 16, 2002, which is a Division of U.S. application Ser. No. 09 / 190,043 filed Nov. 10, 1998 and issued as U.S. Pat. No. 6,391,856 which claims priority from Provisional Application Ser. No. 60 / 065,336 filed Nov. 13, 1997.FIELD OF THE INVENTION[0002]This invention relates to small peptides having mast cell degranulation inhibition activity and to methods for treating inflammation, and particularly to N-formyl-methionyl peptides useful for the treatment of allergies such as allergic rhinitis, uticaria, anaphylaxis, drug sensitivity, food sensitivity, and the like, cutaneous inflammation such as dermatitis, eczema, psoriasis, contact dermatitis, sunburn, aging, and the like, and arthritis such as osteoarthritis, psoriatic arthritis, lupus, spondylarthritis, and the like. These peptides also are useful for treating chronic obstruction pulmonary disease and chronic inflammatory bowel ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/06A61K38/07A61K45/00A61K38/00A61P11/06A61P19/02A61P29/00A61P37/02A61P43/00C07K5/08C07K5/083C07K5/10C07K5/103C07K7/06
CPCA61K38/00C07K5/081C07K5/1013A61K45/06A61K38/07A61K38/08C07K7/06A61P1/00A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P19/02A61P29/00A61P37/02A61P37/08A61P43/00A61K38/06
Inventor HOUCK, JOHN C.CLAGETT, JAMESMACDONALD, MARY
Owner HOUCK JOHN C
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