Description:FIELD OF INVENTION
The present invention relates to compounds that are glucagon –receptor selective peptides.
BACKGROUND OF INVENTION
Obesity is major growing health issue worldwide associated with life threatening disease such as respiratory dysfunction, hypertension, stroke, infertility, and type 2 diabetes. The main cause of obesity is the imbalance between calorie intake and burn rate, also this includes a diet with high fat content and reduced physical activity due to the nature of modern lifestyle and increased urbanization.
Glucagon and glucagon like peptide 1 (GLP-1) are widely involved various physiological functions such as glucose homeostasis, insulin secretion, intestinal growth, regulation of food intake and gastric emptying. GLP-1 is secreted from pre-proglucagon to form a number of different proglucagon derived peptides such as glucagon, GLP-1, GLP-2 and oxyntomodulin (OXM). The pre-proglucagon molecule is a high molecular weight precursor molecule is synthesized in pancreatic alpha cells and in the jejunum and colon L cells. Pre-proglucagon is a 180 amino acid long prohormone and its sequence contains, in addition to glucagon, two sequences of related structure: glucagon-like peptide -1 (GLP-1) and GLP-2. Intervening peptide-2 (IP2) is a 17 amino acid peptide sequence that exists between GLP-1 & GLP-2 and is normally cleaved proteolitically after aa 37 of GLP-1. The processing occurs in pancreas and the intestine. GLP-1 sequence can be further proteolitically processed into active GLP-1, the 31 amino acid processed form, or GLP-1 amide.
Glucagon hormone helps stimulating gluconeogenesis and promoting breakdown of glycogen in liver. When liver-stored glycogen becomes depleted, glucagon stimulates liver and kidney to synthesis new glucose. This affects the appetite suppression and breaking down of triglyceride storage into fatty acids causing increased metabolism thereby affecting weight loss. GLP-1 is a glucagon derivative peptide hormone, secreted from L cells in small intestine after food intake with half-life of 2 minutes and this is responsible for reducing blood glucose and improving beta cells function.
GLP-1 amide and its non-amidated analogue have attracted considerable interest because of the potent actions on carbohydrate metabolism and potential applicability to treat diabetes. GLP-1 amide or GLP-1 is short lived in serum. The peptide in cleaved by dipeptidyl peptidase IV (DPP-IV) between residues 8 & 9 and it becomes in active. Hence, GLP-1, administered exogenously is extremely short lived and has limited utility in therapeutic applications.
Liraglutide is a long acting human GLP-1 derivative developed by Novo Nordisk to treat type 2 diabetes and obesity. It binds to the same receptor as endogenous GLP-1, stimulating insulin secretion, thereby modulating blood glucose level, reducing appetite, lowering triglycerides and suppressing weight gain. Exenatide, dulaglutide, albiglutide and lixisenatide have been developed as antidiabetic drugs.
Semaglutide and other variants are a fragment of the naturally occurring human glucagon-like peptide-1 sequence position 7-37 (GLP-1) and with addition of a fatty acid chain (palmitoyl group on Lys). Semaglutide higher cost drug protocol higher dosage from protein chemical formula Liraglutide C172H265N43O51 and Semaglutide C187H291N45O59 protein average weight 3751.2 Da and 4113.64 Da on the other hand, long peptide-based drugs generally suffer from short half-lives due to proteolytic degradation and fast renal clearance, which require high cost and higher doses/frequency of injections liraglutide 0.6 mg, for once- 1 day and semaglutide 0.25 mg, for once-7 days. There are various drawbacks associated with the administration of semaglutide in patients that include low stability, half-life and bio availability. GLP1 Receptor binds with its GLU-128 to Liraglutide and Semaglutide LYS-26 at 3.0 Å and GLP1 Receptor functional site position of ARG-121 and GLU-128 are mutagenesis. High number of doses / frequency of injections and high cost makes the usage of existing GLP-1 agonists limited. Reports have shown that higher doses and long term administration leads to thyroid cancer and other diseases.
In this project proposal aims at the development of generally applicable technologies bioinformatics, biotechnology, molecular biology & solid phase peptide synthesis (SPPS) that will be applied to a novel target protein glucagon, low cost is not in the market yet to facilitate novel new peptides effective vial or drugs based on specific biological targets for the treatment of type-2 diabetes and other diseases. Since type-2 diabetes and other related diseases is a major threat to our society, the novel peptides effective vial or drugs based on specific biological targets based glucagon produce different profile of secondary metabolites. It may alter the biosynthetic pathway, weather they produce new pharmacologically active compound natural products from readily available natural amino acids through solid phase or solution phase chemistry product based synthetic peptide new vial or drugs from glucagon proteins. The supply base of peptides based vial or drugs used in the manufacture of medicines in largely from the wild. This wild source is speedily shrinking day by day. Therefore, there is a need for alternative source. To develop new innovative interdisciplinary strategies to open new avenues for the development of specific new peptide vial or synthetic peptides powder new drugs.

SUMMARY OF INVENTION
Provided herein are methods of preventing and treating diabetes, obesity and related conditions in patients comprising administering GLP-1 or glucagon agonist peptides.
In one instance, a method of reducing body weight comprises administering to a human subject in need thereof 80-160 µg or160-320 µg of a peptide comprising the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107. .
In one instance, the peptide comprises, consists essentially of, or consists of amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107.
In one instance, the peptide is administered once in 8 days. In one instance, the LYSilirag-1 peptide is administered once in eight days.
In one instance, GLP1R binds with its Glu-125 to biobetter LYSilirag-1 LYS-26 at 2.60 Å
In one instance, GLP1R functional site position of GLU-125 and LYS-130 are not mutagenic.
In one instance, the half-life of the LYSilirag-1 peptide is about for once -8 days to about 192 hours.
In one instance, high stability, half-life and bio availability. Low number of doses / less frequency of injections and low cost makes the usage of existing GLP-1 agonists limited. Reports will show that lower doses and short term administration reduce the thyroid cancer and other diseases.
In one instance, the peptide is administered for at least one week, for at least two weeks, for at least three weeks, or for at least four weeks.
In one instance, the peptide is administered by injection, in one instance the administration in subcutaneous.
In one instance, the peptide is an agonist of GLP-1 activity, an agonist of glucagon activity, or an agonist of both GLP-1 and glucagon activity.
In one instance, the subject is overweight and has hypertension, type 2 diabetes mellitus, dyslipidemia, a history of cardiovascular disease or a combination of thereof.

DETAILED DESCRIPTION
The present invention relates to design of novel GLP-1 peptide that are useful in the treatment of type2 diabetes.
The term “inventive peptide” as used herein as a peptide herein, a variant, an analog, a fragment or a derivative thereof. The term GLP-1 peptide” as used herein means GLP-1 whereas “modified GLP-1 peptide” is intended to mean any GLP-1 analogue, a GLP-1 derivative, a GLP-1 variant, or GLP-1 fragment including a derivatized fragment, analog, or variant of GLP-1. Within the meaning of the present invention any variant, analog, fragment or derivative has to be functional, eg., has to exert the same or a similar biological effects as the unmodified GLP-1 peptide.
In a preferred embodiment of the present invention, the inventive peptide is a peptide or a variant, analog, fragment or derivative thereof, contains a sequence having at least 80%, more preferably at least 85 % and even more preferably at least 90% sequence homology with SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107.
Preferably, the inventive peptide is an amino acid sequence of GLP-1 (length of 31 amino acids) which is strictly conserved among mammalians.
In a preferred embodiment of the present invention, an inventive peptide, i.e. a peptide or its analog, fragment, variant or derivatives, comprises at least 4, preferably at least 10, more preferably at least 20 additional amino acids residues of the unmodified GLP-1 sequence of any mammalian organism.
In a preferred embodiment of the present invention, the inventive peptide may also contain amino acid substitutions, made e.g. with the intention of improving solubility. In one embodiment of variant/ analogs of the GLP-1 peptide of the inventive peptide the modified GLP-1 peptide is characterized by one or more substitutions at positions 7, 8, 11, 12, 16, 22, 23, 24, 25, 27, 30, 33, 34, 35, 36, or 37 of the GLP-1 peptide.
According to a further aspect f the invention there is a provided a methods of treatment of an animal, preferably a human being, by administration of an inventive peptide. It is also provided corresponding use of such inventive peptides in the manufacture of a product for the treatment or prevention of a disease or condition associate with glucose metabolism.
Non-limiting examples of glucose disorder include: diabetes mellitus type I or type Il (NIDDM), or insulin resistance, weight disorders and diseases or conditions associated thereto, wherein such weight disorders or associated conditions include obesity, overweight-associated conditions, satiety deregulation, reduced plasma insulin levels, increased blood glucose levels, or reduced pancreatic beta cell mass. Preferably, use of inventive peptides for the manufacture of a medicament for the treatment of type 2 diabetes (NIDDM) is disclosed herewith. As a consequence, the present invention relates to a use of the inventive peptide e.g. for lowering weight of a subject, for reducing satiety of a subject, for post- prandially increasing plasma insulin levels in a subject, for reducing fasting blood glucose level in a subject, for increasing pancreatic beta cell mass in a subject or for treating diabetes type I or Il in a subject.
Patients with other diseases or disorders may be treated by inventive peptides, i.e. fusion peptides or its analogs, fragments, variants or derivatives, as well. Inventive peptides may be used for the preparation of a medicament for the treatment of neurodegenerative disorders and diseases or conditions associated thereto and for the treatment of disorders and diseases or conditions associated to apoptosis. The use of the inventive peptide for treating these disorders results from the following: GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. The chemoarchitecture of receptor distribution in the brain does not only correlate with a central role for GLP-1 in the regulation of food intake and response to aversive stress. It was also shown that GLP-1 binding at its GLP-1 receptor exerts neurotrophic properties, and offer protection against glutamate-induced apoptosis and oxidative injury in cultured neuronal cells. Furthermore, GLP-1 was shown to modify processing of the amyloid ß-protein precursor in cell culture and dose-dependently reduces amyloid ß-peptide levels in the brain in vivo. GLP-1 is therefore also known as regulator of the central nervous system. Inventive peptides mimicking the biological activity of physiologically active GLP-1 have therapeutic relevance to the treatment of e.g. Alzheimer’s disease (AD) and other central and peripheral neurodegenerative conditions (e.g. amyotrophic lateral sclerosis (ALS), Alexander disease, Alper’s disease, Ataxia telangiectasia, Canavan disease, Cockayne syndrome, Creutzfeldt-Jakob disease, Multiple Sclerosis, Sandhoff disease, Pick’s disease, Spinocerebellar Ataxia, Schilder’s disease and Parkin- son’s disease).
, Claims:We claim:
1. A synthetic peptide analogue for GLP1R comprises an amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107.
2. A synthetic peptide as claimed in claim 1, is a method of reducing body weight administering to a human subject in need thereof 80 µg of a LYSilirag-1 peptide comprising an amino acid sequence from the sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107..
3. A synthetic peptide as claimed in claim 1, is a method of treating obesity comprising administering to a human subject in need thereof 160 µg of a LYSilirag-1 peptide comprising an amino acid sequence from the sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107.
4. A synthetic peptide as claimed in claim 1, is a method of treating obesity comprising administering to a human subject in need thereof 320 µg of a LYSilirag-1 peptide comprising an amino acid sequence from the sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107.
5. A method of half-life of the LYSilirag-1 peptide is about for once in 8 days to about 192 hours.
6. A method of GLP1R binds with its Glu-125 to biobetter LYSilirag-1 LYS-26 at 2.60 Å and GLP1 Receptor functional site mode of action (MOA) position of GLU-125 and LYS-130 are not mutagenic.
7. A method of claim 1-6, wherein the subject has diabetes and obese.
8. A method of claim 6, wherein the diabetes is type 2 diabetes mellitus and obese.
9. A method of any one of claims 1-7, wherein the administration comprises administering an initial dose for 8 days to about 192 hours.
10. A method of claim 8, wherein the initial dose is administered for per 8 days once.
11. A method of claim 9, wherein the initial different dose is administered for per 8 days once 80 µg/160 µg /320 µg of the LYSilirag-1 peptide.
12. A method of any claims, wherein the half-life of the LYSilirag-1 peptide is about 192 hours.