Interleukin-1 receptor antagonists, compositions, and methods of treatment

Abstract

Peptides that are designed to inhibit the biological activity of the IL-1R type 1 receptor and inhibit IL-1R / IL-1RacP related cell signaling and biological activity are disclosed. Compositions comprising IL-1R antagonists of the present invention are useful in the treatment of IL-1 related diseases or conditions such as arthritis, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease as well as other chronic or acute inflammatory diseases. This invention also discloses an isolated compound having an IL-1R antagonist activity, said compound being selected from the group consisting of: a peptide comprising the amino acid sequence RYTPELX, wherein R, Y, T, P, E, L, refer to their corresponding amino acids, and X is selected from no amino acid and alanine (A); and a derivative of (a) wherein the derivative incorporates one, two or three amino acid modification selected from an amino acid addition, deletion or substitution in the RYTPEL portion of the peptide, and wherein said derivative maintains its antagonist IL-1R activity.

Description

FIELD OF THE INVENTION[0001]The present invention relates to IL-1 receptor antagonists and methods of modulating IL-1 receptors activity with same. More specifically, the present invention is concerned with extracellular, non-competitive IL-1 receptor (IL1R / IL1RAcP) peptides and peptidomimetic antagonists, their identification and their therapeutic uses. More particularly, the present invention relates to peptide and peptidomimetic antagonists for use in the treatment of IL-1 associated diseases such as rheumatoid arthritis and inflammatory bowel disease. The present invention has application in the field of biochemistry and medicinal chemistry.BACKGROUND OF THE INVENTION[0002]Cytokines are generic terms for designating biologically active hormone-like proteins (interleukins, interferons, tumor necrosis factor, growth factors) that mediate their effects through a superfamily of receptors. Cytokines and their receptors constitute a powerful control network by which cells signal and c...

AI Technical Summary

Benefits of technology

[0021]In a related embodiment, the antagonists of the present invention are advantageously simple to synthesize.

[0023]Without being limited to a particular theory, IL-1 receptor antagonists may promote or stabilize a particular conformation of the IL-1 receptor, which results in inhibition, of the receptor activity. The peptides, peptide derivatives and peptidomimetics of the present invention inhibit IL-1 dependent intracellular signaling in a non-competitive way. These peptides effectively prevent activation of the intracellular receptor domains responsible for IL-1 receptor signaling. Subsequent cell transduction events leading to expression of molecules (e.g., inflammatory molecules like cytokines, cytokines receptors, prostaglandins, collagenase secretion . . . etc) responsible in part for disease expression are thereby prevented.

[0026]The method of treatment of the present invention may be preventive and reduce the risk of developing an IL-1 associated disease or condition, and may be used to alleviate or obviate the condition. The administration of the therapeutic agent can be in any pharmaceutically acceptable form in a suitable carrier, and in therapeutically acceptable dose.

[0028]The present invention also concerns non-competitive, efficient and selective extracellular receptor agonists. In addition, the invention relates to the use of the non-competitive and selective agonists of the present invention in the treatment of interleukin-associated diseases in which the interleukin-1 (IL) already displays an inflammatory activity or other activity, one or more of an agonist of the present invention increasing the activity of the IL having the above-mentioned anti-inflammatory activity, or other activity. In a related embodiment, the agonists of the present invention are advantageously simple to synthesize. Non-limiting examples of agonists in accordance with the present invention include peptides TTI-101.101 (SEQ ID NO:13) and TTI-101.102 (SEQ ID NO:14) as well as peptidomimetic TTI-101-137 and TTI-101-142 (FIGS. 29 and 30, respectively).

[0032](3) The IL-10 cytokines family: All of this family as a beneficial effect on the inflammation site and its anti-inflammatory effect has been described in the case of wound healing, inflammatory bowel disease and psoriasis. IL-10 decreases the production of pro-inflammatory factors like IL-2, TNF-alpha and IFN-gamma in Th1 cells. It decreases tumor growth by inhibiting the infiltration of macrophages on tumor site (Li et al. 2004; Asadullah et al. 2004).

[0066]Although the present invention is examplified by the specific peptidomimetics of FIGS. 20 and 21, as well as those exemplified in FIGS. 26 to 30, the present invention is not so limited. Based on the disclosure herein, one skilled in the art can readily derive peptidomimetics having antagonistic activity toward the IL-1 receptor, identify further IL-1R / IL-1RacP receptor inhibiting compounds or improve those examplified herein. The peptidomimetics of the present invention are less susceptible to degradation by endogenous proteases and therefore have a longer half-life in vivo.

Problems solved by technology

Despite its normally beneficial effects on an organism response to infection and injury, circumstances have come to light in which the actions of IL-1 are harmful.

The treatments available for these pathologies are currently limited.

They often result in toxicity and secondary effects.

Antagonists of the prior art are either competitive (e.g. soluble receptors, antibodies, cytokine mimetics), most often costly to produce or difficult to apply in vivo (e.g., antisense).

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