Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1994-11-09
2001-06-12
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S016700, C514S017400, C514S018700, C530S317000, C530S322000, C530S328000, C530S329000, C530S330000
Reexamination Certificate
active
06245738
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the fields of peptide chemistry and molecular pathology and, more specifically, to novel cytokine restraining agents.
2. Background Information
Cytokines are a class of proteins produced by macrophages and monocytes in response to viral or bacterial infection and in response to T cell stimulation during an immune response. Cytokines are normally present in very low concentrations in a tissue and mediate their effects through binding to high affinity receptors on specific cell types.
Various cytokines such as the interleukins (IL), interferons (IF) and tumor necrosis factor (TNF) are produced during immune and inflammatory responses and control various aspects of these responses. Following induction of an immune or inflammatory response, the concentrations of the various cytokines increase at different times. For example, following exposure of a subject to bacterial endotoxin, TNF and interleukin-6 (IL-6) levels increase, followed a few hours later by increases in the levels of IL-1 and IL-8.
TNF, IL-1, IL-6 and IL-8 mediate host defense responses, cell regulation and cell differentiation. For example, these cytokines can induce fever in a subject, cause activation of T and B cells and affect the levels of other cytokines, which result in a cascade effect whereby other cytokines mediate the biological action of the first cytokine.
The activation of these four cytokines is responsible for the tissue damage and pain that occurs in various inflammatory conditions including, for example, rheumatoid arthritis. In rheumatoid arthritis, levels of TNF, IL-1, IL-6 and IL-8 increase dramatically and can be detected in the synovial fluid. The cytokine cascade induced by expression of these cytokines results in depressed lipoprotein metabolism as well as bone and cartilage destruction. In bacterial infections, cytokines such as IL-8 act as a signal that attracts white blood cells such as neutrophils to the region of cytokine expression. In general, the release of enzymes and superoxide anions by neutrophils is essential for destroying the infecting bacteria. However, if cytokine expression causes neutrophils to invade, for example, the lungs, release of neutrophil enzymes and superoxide anion can result in the development of adult respiratory distress syndrome, which can be lethal. Similarly, neutrophil invasion in response to cytokine expression in other tissues and organs can lead to destruction of healthy tissue.
Cytokines have multiple biological activities and interact with more than one cell type. In addition, some cells interact with more than one type of cytokine. As a result, it has not been possible to prevent damage to healthy tissue by targeting one particular cytokine or cell type. For example, individual cytokine receptors or receptor antagonists that were designed to eliminate the biological effect due to one cytokine did not decrease mortality due to endotoxic shock, which is mediated by TNF, IL-1, IL-6 and IL-8.
A better approach for preventing tissue damage due to cytokines would be to restrain the expression of all or several of the cytokines involved in the response, without eliminating expression of any cytokine in its entirety. In this way, complete immunosuppression can be prevented and homeostasis can be maintained. Corticosteroids effectively modulate cytokine expression. However, corticosteroids can cause complete immunosuppression and have other undesirable side effects such as inducing “wasting” syndrome, diabetes and osteoporosis. Non-steroidal anti-inflammatory drugs such as ketorolac (Toradol®; Syntex) also are effective in treating inflammation and pain. However, these drugs act by inhibiting prostaglandin production, which can lead to potentially severe complications including gastric ulceration, bleeding and renal failure.
In order to prevent pathological conditions caused by the expression of cytokines, it would be advantageous if cytokine levels could be readily controlled in a tissue. However, modifying the physiologic effect of cytokines has been hindered due to their pleiotropic effects. Thus, a need exists for agents that can restrain the activity of cytokines in a subject without causing undesirable side effects. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention relates to novel peptides that are potent cytokine restraining agents. Novel cytokine restraining peptides having the general structures, X
1
-X
2
-His-(D)Phe-Arg-(D)Trp-X
3
and X
4
-His-(D)Phe-Arg-(D)Trp-X
3
, where X
1
, X
2
, X
3
and X
4
can be amino acids or amino acid analogs, are disclosed. The invention also relates to a cytokine restraining peptide having the structure, Ac-His-(D)Phe-Arg-(D)Trp(Ch
2
NHAc)-Gly-NH
2
, which contains a (D)Trp analog.
In addition, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a cytokine restraining agent and to methods of administering the pharmaceutical composition to a subject. Administration of such a cytokine restraining agent to a subject restrains, but does not completely suppress, cytokine activity. Thus, the present invention provides a method for preventing or minimizing damage to healthy tissue caused by cytokine activity in a subject without causing complete immunosuppression in the subject.
DETAILED DESCRIPTION OF THE INVENTION
The present invention generally relates to novel cytokine restraining agents having the structure; X
1
-X
2
-His-(D)Phe-Arg-(D)Trp-X
3
, wherein
X
1
is
H or COCH
3
;
X
2
is
and
X
3
is
NH
2
or OH;
wherein Y is O, B
2
or S; R
1
is H, COCH
3
, C
2
H
5
, CH
2
Ph, COPh, COO-t-butyl, COOCH
2
Ph, CH
2
CO-(polyethylene glycol) or A; R
2
is H or COCH
3
; R
3
is a linear or branched alkyl group having 1 to 6 carbon atoms or a cyclic alkyl group having 3 to 6 carbon atoms; R
4
is (CH
2
)
m
—CONH
2
, (CH
2
)
m
—CONHR
1
or (CH
2
)
m
—CONHA; R
5
is OH, OR
3
, NH
2
, SH, NHCH
3
, NHCH
2
Ph or A; and R
6
is H or R
3
;
and wherein “Ph” is C
6
H
5
, “m” is 1, 2 or 3, “n” is 0, 1, 2 or 3, and “A” is a carbohydrate having the general formula:
For example, the invention provides peptides such as Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
; Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
; and Ac-(cyclohexyl) Gly-Gln-His-(D)Phe-Arg-(D) Trp-Gly-NH
2
, which can restrain cytokine activity.
The present invention also relates to novel cytokine restraining agents having the structure: X
4
-His-(D)Phe-Arg-(D)Trp-X
3
, wherein
X
4
is
H or COCH
3
; and
X
3
is
NH
2
or OH;
wherein Y is O, H
2
or S; R
1
is H, COCH
3
, C
2
H
5
, CH
2
Ph, COPh, COO-t-butyl, COOCH
2
Ph, CH
2
CO-(polyethylene glycol) or A; R
2
is H or COCH
3
; R
4
is (CH
2
)
m
—CONH
2
, (CH
2
)
m
—CONHR
1
or (CH
2
)
m
—CONHA; R
5
is OH, OR
3
, NH
2
, SH, NHCH
3
, NHCH
2
Ph or A; and R
6
is H or R
3
;
and wherein “Ph” is C
6
H
5
, “m” is 1, 2 or 3, “n” is 0, 1, 2 or 3, and “A” is a carbohydrate having the general formula
For example, the invention provides His-(D)Phe-Arg-(D)Trp-Gly-NH
2
; Ac-His-(D)Phe-Arg-(D)Trp-NH
2
; His-(D)Phe-Arg-(D)Trp-OH; and cyclo(His-(D)Phe-Arg-(D)Trp), which can restrain cytokine activity.
As used herein, the term “restrain” has its commonly understood meaning, i.e., to limit, restrict, keep under control or moderate. It follows that a “cytokine restraining agent” is an agent that has an action that limits or controls the biological activity of a cytokine. A cytokine restraining agent can be, for example, a peptide comprising amino acids or amino acid analogs as described herein. In addition to the examples provided above, other representative examples of peptide cytokine restraining agents include:
1) Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-OH;
2) Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-OC
2
H
5
;
3) Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH-NH
2
;
4) Ac-Nle-Asn-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
;
5) Ac-Nle-Asn-His-(D)Phe-Arg-(D)Trp-Gly-OH;
6) Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NHCH
2
CH
2
Ph;
Girten Beverly E.
Houghten Richard A.
Loullis Costas C.
Suto Mark J.
Tuttle Ronald R.
Campbell & Flores LLP
Gupta Anish
Low Christopher S. F.
Trega Biosciences, Inc.
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