Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-12-05
2004-11-16
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S094600, C424S192100, C530S300000, C435S068100, C435S069700
Reexamination Certificate
active
06818611
ABSTRACT:
BACKGROUND OF THE INVENTION
Bioactive peptides are small peptides that elicit a biological activity. Since the discovery of secretin in 1902, over 500 of these peptides which average 20 amino acids in size have been identified and characterized. They have been isolated from a variety of systems, exhibit a wide range of actions, and have been utilized as therapeutic agents in the field of medicine and as diagnostic tools in both basic and applied research. Tables 1 and 2 list some of the best known bioactive peptides.
TABLE 1
Bioactive peptides utilized in medicine
Size In
Amino
Name
Isolated From
Acids
Therapeutic Use
Angiotensin II
Human Plasma
8
Vasoconstrictor
Bradykinin
Human Plasma
9
Vasodilator
Caerulein
Frog Skin
10
Choleretic Agent
Calcitonin
Human Parathyroid
32
Calcium Regulator
Gland
Cholecystokinin
Porcine Intestine
33
Cholerectic Agent
Corticotropin
Porcine Pituitary
39
Hormone
Gland
Eledoisin
Octoped Venom
11
Hypotensive Agent
Gastrin
Porcine Stomach
17
Gastric Activator
Glucagon
Porcine Pancreas
29
Antidiabetic Agent
Gramicidin D
Bacillus brevis
11
Antibacterial Agent
Bacteria
Insulin
Canine Pancreas
Antidiabetic Agent
Insulin A
21
Insulin B
30
Kallidin
Human Plasma
10
Vasodilator
Luteinizing
Bovine Hypo-
10
Hormone Stimulator
thalamus
Hormone-
Releasing Factor
Melittin
Bee Venom
26
Antirheumatic Agent
Oxytocin
Bovine Pituitary
9
Oxytocic Agent
Gland
Secretin
Canine Intestine
27
Hormone
Sermorelin
Human Pancreas
29
Hormone Stimulator
Somatostatin
Bovine Hypo-
14
Hormone Inhibitor
thalamus
Vasopressin
Bovine Pituitary
9
Antidiuretic Agent
Gland
TABLE 2
Bioactive peptides utilized in applied research
Size In
Amino
Biological
Name
Isolated From
Acids
Activity
Atrial Natriuretic
Rat Atria
28
Natriuretic Agent
Peptide
Bombesin
Frog Skin
14
Gastric Activator
Conamokin G
Snail Venom
17
Neurotransmitter
Conotoxin Gl
Snail Venom
13
Neuromuscular
Inhibitor
Defensin HNP-1
Human Neutrophils
30
Antimicrobal
Agent
Delta Sleep-
Rabbit Brain
9
Neurological
Affector
Inducing
Peptide
Dermaseptin
Frog Skin
34
Antimicrobial
Agent
Dynorphin
Porcine Brain
17
Neurotransmitter
EET1 II
Ecballium elaterium
29
Protease Inhibitor
seeds
Endorphin
Human Brain
30
Neurotransmitter
Enkephalin
Human Brain
5
Neurotransmitter
Histatin 5
Human Saliva
24
Antibacterial
Agent
Mastoparan
Vespid
Wasps
14
Mast Cell
Degranulator
Magainin 1
Frog Skin
23
Antimicrobial
Agent
Melanocyte
Porcine Pituitary Gland
13
Hormone
Stimulating
Stimulator
Hormone
Motilin
Canine Intestine
22
Gastric Activator
Neurotensin
Bovine Brain
13
Neurotransmitter
Physalaemin
Frog Skin
11
Hypotensive
Agent
Substance P
Horse Intestine
11
Vasodilator
Vasoactive
Porcine Intestine
28
Hormone
Intestinal
Peptide
Where the mode of action of these peptides has been determined, it has been found to be due to the interaction of the bioactive peptide with a specific protein target. In most of the cases, the bioactive peptide acts by binding to and inactivating its protein target with extremely high specificities. Binding constants of these peptides for their protein targets typically have been determined to be in the nanomolar (nM, 10
−9
M) range with binding constants as high as 10
−12
M (picomolar range) having been reported. Table 3 shows target proteins inactivated by several different bioactive peptides as well as the binding constants associated with binding thereto.
TABLE 3
Binding constants of bioactive peptides
Size in
Bioactive
Amino
Inhibited
Binding
Peptide
Acids
Protein
Constant
&agr;-Conotoxim
15
Nicotinic Acetylcholine
1.0 × 10
−9
M
GIA
EET1 II
29
Trypsin
1.0 × 10
−12
M
H2 (7-15)
8
HSV Ribonucleotide
3.6 × 10
−5
M
Reductase
Histatin 5
24
Bacteroides gingivalis
5.5 × 10
−8
M
Protease
Melittin
26
Calmodulin
3.0 × 10
−9
M
Myotoxin (29-42)
14
ATPase
1.9 × 10
−5
M
Neurotensin
13
Ni Regulatory Protein
5.6 × 10
−11
M
Pituitary Adenylate
38
Calmodulin
1.5 × 10
−8
M
Cyclase Activating
Polypeptide
PKI (5-24)
20
cAMP-Dependent
2.3 × 10
−9
M
SCP (153-180)
27
Protein Calpain
3.0 × 10
−8
M
Secretin
27
HSR G Protein
3.2 × 10
−9
M
Vasocactive
28
GPRN1 G Protein
1.5 × 10
−9
M
Intestinal
Peptide
Recently, there has been an increasing interest in employing synthetically derived bioactive peptides as novel pharmaceutical agents due to the impressive ability of the naturally occurring peptides to bind to and inhibit specific protein targets. Synthetically derived peptides could be useful in the development of new antibacterial, antiviral, and anticancer agents. Examples of synthetically derived antibacterial or antiviral peptide agents would be those capable of binding to and preventing bacterial or viral surface proteins from interacting with their host cell receptors, or preventing the action of specific toxin or protease proteins. Examples of anticancer agents would include synthetically derived peptides that could bind to and prevent the action of specific oncogenic proteins.
To date, novel bioactive peptides have been engineered through the use of two different in vitro approaches. The first approach produces candidate peptides by chemically synthesizing a randomized library of 6-10 amino acid peptides (J. Eichler et al., Med. Res. Rev. 15:481-496 (1995); K. Lam, Anticancer Drug Des. 12:145-167 (1996); M. Lebl et al., Methods Enzymol. 289:336-392 (1997)). In the second approach, candidate peptides are synthesized by cloning a randomized oligonucleotide library into a Ff filamentous phage gene, which allows peptides that are much larger in size to be expressed on the surface of the bacteriophage (H. Lowman, Ann. Rev. Biophys. Biomol. Struct. 26:401-424 (1997); G. Smith et al., et al. Meth. Enz. 217:228-257 (1993)). To date, randomized peptide libraries up to 38 amino acids in length have been made, and longer peptides are likely achievable using this system. The peptide libraries that are produced using either of these strategies are then typically mixed with a preselected matrix-bound protein target. Peptides that bind are eluted, and their sequences are determined. From this information new peptides are synthesized and their inhibitory properties are determined. This is a tedious process that only screens for one biological activity at a time.
Although these in vitro approaches show promise, the use of synthetically derived peptides has not yet become a mainstay in the pharmaceutical industry. The primary obstacle remaining is that of peptide instability within the biological system of interest as evidenced by the unwanted degradation of potential peptide drugs by proteases and/or peptidases in the host cells. There are three major classes of peptidases which can degrade larger peptides: amino and carboxy exopeptidases which act at either the amino or the carboxy terminal end of the peptide, respectively, and endopeptidases which act on an internal portion of the peptide. Aminopeptidases, carboxypeptidases, and endopeptidases have been identified in both prokaryotic and eukaryotic cells. Many of those that have been extensively characterized were found to function similarly in both cell types. Interestingly, in both prokaryotic and eukaryotic systems, many more arninopeptidases than carboxypeptidases have been identified to date.
Approaches used to address the problem of peptide degradation have included the use of D-amino acids or modified amino acids as opposed to the naturally occurring L-amino acids (e.g., J. Eichler et al., Med Res Rev. 15:481-496 (1995); L. Sanders, Eur. J. Drug Metabol. Pharmacokinetics 15: 95-102 (1990)), the use of cyclized peptides (e.g., R. Egleton, et al., Peptides 18: 1431-1439 (1997)), and the development of enhanced delivery systems that prevent degradation of a peptide before it reaches its target in a patient (e.g., L. Wearley, Crit. Rev. Ther. Drug Carrier Syst. 8: 331-394 (1991); L. Sanders, Eur. J. Drug Metabol. Pharmacokinetics 15: 95-102 (1990)). Although these approaches for stabilizing peptides and thereby preventing their unwanted
Carlson Karen Cochrane
Liu Samuel Wei
Mueting Raasch & Gebhardt, P.A.
University of Georgia Research Foundation Inc.
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