Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-01-14
2001-09-11
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S011400, C514S012200, C514S015800
Reexamination Certificate
active
06288029
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a new type of agonist that interacts preferentially with the neuropeptide Y (NPY) Y2 receptor. The agonist contains one or more peptides with sequences from the C-terminal end of neuropeptide Y (NPY) or peptide YY (PYY) bound to a template that promotes the correct folding of these peptides. In addition, the present invention is directed to methods for reducing airway resistance in bronchial patients by administering NPY, PYY, or agonists of these peptides.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) is an amidated peptide widely distributed in the central and peripheral nervous systems (Tatemoto, et al.,
Nature
296:659-660 (1982); Ekblad, et al.,
Regul. Peptides
8:225-235 (1984)). It is present in all sympathetic nerves innervating the cardiovascular system and is the most abundant peptide in the brain and the heart (Tatemoto, et al.,
Nature
296:659-660 (1982)). In addition, NPY is present in platelets (Ericsson, et al.,
Proc. Natl. Acad. Sci. U.S.A.
84:5587-5591 (1987)), the endothelium (Id.); the adrenal medulla (Allen, et al.,
J. Auton. Nerv. Sys.
9:559-566 (1983)); the pancreas (Jamal, et al.,
Endocrinology
129:3372-3380 (1991)); the kidney (Grouzmann, et al.,
Peptides
15 (8):1377-1382 (1994)); and the pituitary gland (Gehlert, et al.,
Peptides
15 (4):651-656 (1994)). Peptide YY (PYY) is a closely related peptide that has similar biological effects to NPY and which is found primarily in the gut.
The biological actions of NPY and peptide YY are mediated by a number of G-protein coupled receptors termed Y1, Y2, Y3, Y4/PP and Y5 (Herzog, et al.,
Proc. Natl. Acad. Sci. U.S.A.
89:5794-5798 (1992)). Of these, the physiological effects associated with the Y1 and Y2 receptors are the best characterized. Exposure to a Y1 agonist causes an increase in blood pressure and potentiates post-synaptically the action of other vasoactive substances (Wahlestedt, et al.,
J. Pharmacol. Exp. Ther.
234:735-741 (1985)). In contrast, Y2 receptors are mainly located presynaptically and, upon stimulation, mediate the inhibition of neurotransmitter release (Westfall, et al.,
J. Cardiovasc. Pharmacol.
10:716-722 (1987)).
NPY has a number of biological effects of potential therapeutic importance. Intranasal administration of NPY reduces nasal airway resistance and vascular permeability without affecting submucosal gland secretion (Baraniuk, et al.,
Am. J. Respir. Cell. Mol. Biol.
3:165-173 (1990); Baraniuk, et al.,
J. Appl. Physiol.
73 (5):1867-72 (1992)). In healthy volunteers, intranasal pretreatment with exogenous NPY markedly reduces vasodilation and nasal secretion induced by afferent nerve stimulation with capsaicin or histamine (Lacroix, et al., Br.
J Pharmacol.
118:2079-2084 (1996)). Therapeutic application of NPY in the treatment of rhinitis has been recently suggested since allergen-evoked nasal responses in patients are significantly attenuated after local pretreatment with the peptide (Lacroix, et al.,
J. Allergy Clin. Immunol.
98:611-616 (1996)).
NPY also plays an important role in modulating the cardiovascular system, behavior, anxiety and the secretion of certain hormones (Wahlestedt, et al.,
Annu. Rev. Pharmacol. Toxicol.
33:309-352 (1993); Michel,
Trends Pharmacol. Sci.
12:389-394 (1991)). It contributes to the central and peripheral control of blood pressure, the regulation of feeding behavior, obesity, diabetes and psychiatric disorders (Walker, et al.,
Trends Pharmacol Sci
12:111-115 (1991); Sahu, et al.,
Trends Endocrinol. Metab.
4:217-224 (1993); Stanley, et al.,
Proc. Natl. Acad. Sci. USA
82:3940-3943 (1985)).
B. Structure of NPY and PYY
NPY is derived from the 97 amino acid precursor shown as SEQ ID NO:1 (Minth, et al.,
Proc. Natl. Acad. Sci. USA
81:4577-4581 (1984)). Amino acids 29-64 represent the 36 amino acid sequence which undergoes processing resulting in the addition of an N-terminal glycine and the amidation of the C-terminal tyrosine. The complete NPY sequence is needed for binding to the Y1 receptor, whereas C-terminal fragments are selective for the Y2 receptor (Ekblad, et al.,
Regul. Peptides
8:225-235 (1984)). The C-terminal pentapeptide amide is important for both receptors and probably represents the binding site (Beck-Sickinger, et al.,
Eur. J. Biochem.
225:947-958 (1994)). However, Arg33 and Arg35 may not be exchanged by L-alanine in the Y1 system, whereas Arg35 and Tyr36 are the most critical residues for the Y2 receptor. NPY fragments shorter than NPY 27-36 are no longer able to bind to the Y2 receptor.
Peptide YY also binds to the Y2 receptor. It is 36 amino acids in length and shares a 70% sequence homology with NPY. Its sequence is shown as SEQ ID NO:2.
C. Template Assembled Synthetic Proteins or Peptides (TASP)
In order to bypass the folding problem that has typically been associated with peptide and protein synthesis, a conceptually different approach to de novo protein design has recently been taken, the synthesis of template-assembled synthetic proteins or peptides (TASP). In this approach, topological templates direct covalently attached peptide blocks to a predetermined three-dimensional packing arrangement (FIGS.
1
-
3
), thereby modifying their biological and pharmacokinetic properties ((Mutter, et al.,
Helv. Chim. Acta,
71:835-47 (1988); Mutter,
Trends Biochem. Sci.,
13:260-5 (1988); Mutter, et al.,
J. Am. Chem. Soc.
114:1463-1470 (1992); Grouzmann, et al.,
Eur. J. Biochem.
234:44-49 (1995)). Typically, templates are constrained peptides, cyclodextrines or polycyclic systems.
Recently, the TASP concept was used to design a compound that selectively antagonizes the action of NPY at the Y2 receptor. A cyclic peptide exhibiting four attachment sites and a naphthyl derivative was used as template and NPY33-36 segments were attached by means of an oxime bond (Grouztnann, et al.,
J. Biol. Chem.
292 (12):7699-7706 (1997)). This TASP molecule was investigated for binding to NPY Y1 and Y2 receptors and its antagonistic activity was established by its ability to prevent the NPY-induced increase in intracellular calcium.
D. TASP Agonists of NPY Y2 Receptor Interaction
It has now been discovered that template assembled synthetic peptides can produce NPY and PYY agonists that interact specifically with the Y2 receptor. These compounds may be used in the treatment of several conditions, including rhinitis. In addition, it has been discovered that NPY, PYY and agonists of these peptides may be used in treating bronchial diseases and related conditions.
SUMMARY OF THE INVENTION
The present invention is based upon two main discoveries. The first is that template assembled synthetic peptides can be produced that are agonists of NPY and PYY. These agonists can be used to effectively treat rhinitis and a variety of other physiological conditions. The second discovery is that NPY, PYY and their agonists reduce bronchial airway resistance. Thus, these agents may be used in treating bronchitis, asthma and related conditions.
In its first aspect, the present invention is directed to an agonist of NPY comprising a template and one or more peptides derived from NPY or PYY covalently bound to the template. The template is a cyclized peptide between 3 and 10 amino acids in length containing at least two residues that are joined by a naphthyl ring. At least one, and preferably two, linear peptides between 12 and 27 amino acids in length are covalently bound to the template, e.g.,by an oxime bond. The C-terminal sequence of the bound peptide(s) has either the sequence: RHYINLITRQRY, (SEQ ID NO:3); or the sequence RHYLNLVTRQRY (SEQ ID NO:4). In either case, the C-terminal tyrosine should be amidated. In a preferred embodiment, linear peptides are attached at the lysine residues of the following template:
The 12 amino acid C-terminal sequences shown above may be preceded by additional portions of the NPY sequence, up to the full additional 24 amino acids found in NPY: YPSKPDNPGEDAPAEDMARYYSAL, (SEQ ID NO:5). For example, SEQ ID NO:3 may be preceded at its N
Grouzmann Eric
Lacroix Jean-Silvain
Mutter Manfred
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