US20170051031A1 - Lipidated peptides as neuroprotective agents - Google Patents
Lipidated peptides as neuroprotective agents Download PDFInfo
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- US20170051031A1 US20170051031A1 US15/307,262 US201515307262A US2017051031A1 US 20170051031 A1 US20170051031 A1 US 20170051031A1 US 201515307262 A US201515307262 A US 201515307262A US 2017051031 A1 US2017051031 A1 US 2017051031A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57554—Prolactin
Definitions
- New analogs of prolactin releasing peptide represent neuroprotective agents for peripheral treatment and prevention of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.
- AD Alzheimer's disease
- PD Parkinson's disease
- CIND cognitive impairment no dementia
- AD Alzheimer's disease
- the disease starts to manifest with memory decline, learning disorders, behavioral changes, impairment in orientation in time and space, loss of autonomic functions, finally results in complete dementia.
- the death comes on average 9 years after diagnosis.
- Histopathologically, AD is characterized by two hallmarks: intracellularar neurofibrilary tangles formed by hyperphosphorylated Tau protein and extracellular senile plaques of beta peptide.
- PrRP Prolactin releasing peptide
- Naturally two isoforms of PrRP can be found in organism: peptide containing 31 amino acids (PrRP/1-31/; PrRP31) or 20 amino acids (PrRP/12-311; PrRP20), its amino acid composition also exhibits small differences in various species (human, rat, bovine) (Hinuma et al., 1998).
- PrRP is produced in neurons of many brain regions, mainly in medulla oblongata (in nucleus tractus solitarius and ventrolateral reticular nucleus), and hypothalamus (in paraventricular and dorsomedial nuclei), less in pituitary gland, and amygdala. In the periphery PrRP can be found in adrenal medulla, testis, pancreas, and small and large intestines.
- PrRP receptor GPR10
- PrRP receptor 10 is extensively expressed in the whole brain; it can be found in anterior pituitary, amygdala, hypothalamus, brainstem, and medulla oblongata. In the periphery GPR10 can be found in adrenal medulla, and significantly increased expression was observed in human and rat pancreas.
- AD Alzheimer's disease
- agents increasing insulin sensitivity such as metformin
- insulin secretagogues such as glucagon-like peptide-1 (GLP-1 gastric-inhibitory peptide (GIP and their analogs could act as AD treatment.
- GLP-1 gastric-inhibitory peptide GLP-1 gastric-inhibitory peptide
- the present invention provides lipidated neuropeptides based on prolactin-releasing peptide (PrRP-based neuropeptides) selected from prolactin-releasing peptide 20 (PrRP20), prolactin-releasing peptide 31 (PrRP31) and their analogs, wherein in the C-terminal sequence IRPVGRF-NH 2 (SEQ ID NO.
- one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid; said PrRP-based neuropeptide containing C14 and/or C16 fatty acid chain, said fatty acid is bound in position 1 or 11 for PrRP31 or its analogs and in position 1 or 7 for PrRP20 or its analogs; said fatty acid being bound by a bond between an amino acid having at least one free NH 2 , OH or SH group and the carboxylic group of the fatty acid or through a hydrophilic linker X 2 selected from the group comprising polyoxyethylene moiety, arylalkyl moiety, or a saturated or unsaturated, linear or branched C 3 -C 8 hydrocarbon chain, wherein some carbon atoms may be replaced by heteroatoms selected from a group comprising N, S, and O; said chain carrying at least one and preferably two amino groups or carboxylic acid groups, one of which may be substituted to form a group selected from: CONH 2 ; NH-polyoxy
- the PrRP31 or its analogs may optionally have the amino acid in position 11 replaced by an amino acid having a free NH 2 , OH or SH group, particularly when the fatty acid is bound in position 11 for PrRP31 or its analogs; and the PrRP20 or its analogs may have the amino acid in position 7 replaced by an amino acid having a free NH 2 , OH or SH group in position 7, particularly when the fatty acid is bound in position 7 for PrRP20 or its analogs; for use in a method of treatment and prevention of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.
- AD Alzheimer's disease
- PD Parkinson's disease
- CIND cognitive impairment no dementia
- PrRP31 and/or PrRP20 include variants found in various animal species. Preferred are the human and rat variants.
- isoleucine can be replaced by phenylglycine or alanine
- valine can be replaced by phenylglycine
- terminal phenylalanine can be replaced by dichlorophenylalanine, pentafluorophenylalanine, nitrophenylalanine, histidine, benzylhistidine, naphthylalanine, tryptofane, pyroglutamic acid, benzylcysteine, benzyl-O-glutamate, tetrachlorophenylalanine, methyl-O-phenylalanine or methyl-NH-phenylalanine.
- the binding of the fatty acid thus includes either a direct bond between an amino acid of the PrRP chain having at least one free amino, SH or OH group and the carboxylic group of the fatty acid, or a bond through X 2 , wherein X 2 is a hydrophilic linker selected from a group comprising polyoxyethylene moiety, arylalkyl moiety, or a saturated or unsaturated, linear or branched C 3 -C 8 hydrocarbon chain, wherein some carbon atoms may be replaced by heteroatoms selected from a group comprising N, S, and O; said chain carrying at least one and preferably two amino groups or carboxylic acid groups, one of which may be substituted to form a group selected from: CONH 2 ; NH-polyoxyethylene; COOM 1 wherein M 1 is alkali metal, preferably Na or K; CN; COOR 1 , COR 1 , or CONHR 1 wherein R 1 is selected from a group comprising lower alkyl, arylalkyl, polyoxyethylene
- X 2 is a hydrophilic linker selected from the group comprising ⁇ -alanine, ⁇ -aminobutyric acid and ⁇ -glutamic acid.
- the PrRP31 or its analogs When the fatty acid is bound in position 11 for PrRP31 or its analogs, the PrRP31 or its analogs have an amino acid having a free NH 2 , OH or SH group in position 11, and when the fatty acid is bound in position 7 for PrRP20 or its analogs, the PrRP20 or its analogs have an amino acid having a free NH 2 , OH or SH group in position 7.
- Amino acids having a free NH 2 , OH or SH group include, for example, lysine, arginine, serine, cysteine, tyrosine.
- the present invention provides, more particularly, the lipidated analogs of PrRP20 or PrRP31 (rat and human) according to the formulae:
- (X)TPD1NPAWYTGRGIRPVGRF-NH 2 wherein X ⁇ X 1 or X 1 X 2 ; X 1 being tetradecanoic or hexadecanoic acid, which is bound in a position 1 to an amino acid of the above mentioned peptide chain either directly or through X 2 , X 2 being a hydrophilic linker as defined above, preferably selected from the group consisting of ⁇ -alanine, ⁇ -amino butyric acid and ⁇ -glutamic acid, and wherein in the C-terminal sequence IRPVGRF-NH 2 , one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid; for use in the treatment and prevention, preferably by peripheral administration, of neurodegenerative diseases, which are Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.
- AD Alzheimer's disease
- PD Parkinson's disease
- lipidated analogs of PrRP20 or PrRP31 according to the formulae:
- TPDINPKWYASRGIRPVGRF-NH 2 TPDINPKWYASRGIRPVGRF-NH 2 ;
- AD Alzheimer's disease
- PD Parkinson's disease
- CIND cognitive impairment no dementia
- a further embodiment of the invention relates to the use of lipidated neuropeptides based on prolactin-releasing peptide (PrRP-based neuropeptides) selected from prolactin-releasing peptide 20 (PrRP20), prolactin-releasing peptide 31 (PrRP31) and their analogs, wherein in the C-terminal sequence IRPVGRF-NH 2 , one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid; said PrRP-based neuropeptide containing C14 and/or C16 fatty acid chain, said fatty acid is bound in position 1 or 11 for PrRP31 or its analogs and in position 1 or 7 for PrRP20 or its analogs; said fatty acid being bound by a bond between an amino acid having at least one free NH 2 , OH or SH group and the carboxylic group of the fatty acid or through a hydrophilic linker X 2 selected from the group comprising polyoxyethylene moiety, arylalkyl moiety
- the PrRP31 or its analogs may have the amino acid in position 11 replaced by an amino acid having a free NH 2 , OH or SH group, particularly when the fatty acid is bound in position 11 for PrRP31 or its analogs; and the PrRP20 or its analogs may have the amino acid in position 7 replaced by an amino acid having a free NH 2 , OH or SH group in position 7, particularly when the fatty acid is bound in position 7 for PrRP20 or its analogs; for the manufacture of a medicament for treatment and prevention of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.
- AD Alzheimer's disease
- PD Parkinson's disease
- CIND cognitive impairment no dementia
- Another embodiment of the invention provides a method of treatment and prevention of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders, comprising a step of administering to a subject in need of such treatment or prevention, preferably by peripheral administration, lipidated neuropeptides based on prolactin-releasing peptide (PrRP-based neuropeptides) selected from prolactin-releasing peptide 20 (PrRP20), prolactin-releasing peptide 31 (PrRP31) and their analogs, wherein in the C-terminal sequence IRPVGRF-NH 2 , one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid; said PrRP-based neuropeptide containing C14 and/or C16 fatty acid chain, said fatty acid is bound in position 1 or 11 for PrRP31 or its analogs and in position 1 or 7 for PrRP20 or its analogs; said fatty acid
- PrRP31 or its analogs may have the amino acid in position 11 replaced by an amino acid having a free NH 2 , OH or SH group, particularly when the fatty acid is bound in position 11 for PrRP31 or its analogs; and the PrRP20 or its analogs may have the amino acid in position 7 replaced by an amino acid having a free NH 2 , OH or SH group in position 7, particularly when the fatty acid is bound in position 7 for PrRP20 or its analogs.
- FIG. 3 shows insulin signaling cascade in hippocampi of 6-month-old MSG obese mice after 14-day treatment with liraglutide and palmitoylated human PrRP31.
- Liraglutide 0.2 mg/kg
- palmitoylated human PrRP31 5 mg/kg
- Phosphorylation was determined using WB.
- Statistical analysis is 1-way ANOVA with Bonferroni post hoc test. Significance is *P ⁇ 0.05 and ***P ⁇ 0.001.
- FIG. 4 shows phosphorylation at different epitopes of Tau protein in hippocampi of 6-month-old MSG mice after 14-day treatment with liraglutide and palmitoylated human PrRP31.
- Liraglutide 0.2 mg/kg
- palmitoylated human PrRP31 5 mg/kg
- Phosphorylation was determined using WB.
- Statistical analysis is 1-way ANOVA with Bonferroni post hoc test. Significance is *P ⁇ 0.05 and ***P ⁇ 0.001.
- FIG. 6 shows immunohistochemical analysis of Tau hyperphosphorylation in CA1 region of the hippocampus of 6-month-old MSG mice and their age-matched controls, and Tau hyperphosphorylation after 14-day treatment with liraglutide and palmitoylated PrRP31.
- Liraglutide (0.2 mg/kg) and palmitoylated human PrRP31 (5 mg/kg) were subcutaneously administered twice a day, in the morning and in the evening. Saline treated mice served as a control. Tau phosphorylation was determined using double immunohistochemical fluorescent staining.
- FIG. 7 shows spatial memory testing of Thy-Tau 22 mice and their WT controls in Y-maze.
- the memory was tested A/ before the beginning of the experiment and B/ after 2-month-long treatment with LiPR31 dissolved in PBS/5% Tween 80 using SC Alzet® osmotic pumps, the concentration was 5 mg/kg/day; PBS/5% Tween 80 was administered to the control group.
- Statistical analysis is Student t-test. Significance is *P ⁇ 0.05.
- FIG. 8 shows Tau phosphorylation after 2-month-long treatment of Thy-Tau22 mice with LiPR31 dissolved in PBS/5% Tween 80 using SC Alzet® osmotic pumps, the concentration was 5 mg/kg/day; PBS/5% Tween 80 was administered to the control group.
- Statistical analysis is Student t-test. Significance is *P ⁇ 0.05.
- Liraglutide was purchased from Novo Nordisk A/S (Bagsvaerd, Denmark).
- insulin resistant animal model e.g. mouse model with obesity induced by MSG. These mice are characterized by growth hormone insufficiency, pituitary and optic nerves atrophy, and infertility (Olney, 1969). In their brains the reduced nucleus arcuatus, enlarged third brain ventricle, and narrowed eminentia mediana are observed. Total number of neurons in ARC is reduced about 75% in MSG mice compared to their controls; however, the number of neurons does not differ significantly in other brain regions (Elefteriou et al., 2003).
- MSG obese mice have even 8 times higher weight of white adipose tissue (Malet ⁇ nská et al., 2006). They have also increased leptin and glucose blood concentration, and insulin resistance (Malet ⁇ nská et al., 2006).
- Thy-Tau22 mice For evaluation of the the neuroprotecitve effect of palmitoylated PrRP LiPR31, the model of AD like pathology, Thy-Tau22 mice, was used. Thy-Tau22 mice overexpress human 4R-Tau protein with mutations G272V and P3015. These mice develop memory deficits, Tau hyper-phosphorylation at different epitopes, such as Ser202, Thr205, Thr212, Ser214, Thr231, Ser396, in CA1 region of hippocampus, and neurofibrillary tangles formation (Schindowski et al., 2006; Van der Jeugd et al., 2011).
- mice of strain NMRI were housed at the certified animal facility of IOCB AS CR, Prague, in the campus of Academy of Science in Kr ⁇ hacek over (c) ⁇ at 22 ⁇ 2° C., they had free access to water and food. They were fed standard chow diet St-1 (Ml ⁇ n Kocanda, Jesenice, Czech Republic), which contained 66% calories as carbohydrates, 25% as protein, and 9% as fat; its energy content was 3.4 kcal/g. Daily cycle was 12/12 hours, lights on at 6:00 a.m. All animal experiments followed the ethical guidelines for animal experiments and the Czech Republic Act No. 246/1992.
- mice For obesity induction, the newborn NMRI mice were SC administered with sodium glutamic acid (Sigma, St. Louis, USA) at dose 4 mg/g of body weight at postnatal days 2-5. These MSG-obese mice were fed the same standard diet as the control group. The food and body weight was monitored once per week. For the study, MSG and control male mice at the age of 2 and 6 months were used.
- sodium glutamic acid Sigma, St. Louis, USA
- the spatial memory was tested using Morris water maze (MWM) following the protocol described in article of Vorheese and Williamse (Vorhees and Williams, 2006) in 6-month-old MSG mice and their age-matched controls.
- MLM Morris water maze
- Thy-Tau22 female mice and their age-matched WT controls were a kind gift from INSERM laboratory, Lille, France, the research group “Alzheimer & Tauopathies”. Mice were obtained at the age of 7 months, and were housed 3-4 per cage in the certified animal facility of the Institute of Physiology AS CR, Prague, Czech Republic, with free access to water and Altromin diet (Altromin, Eastern-Westphalia, Germany). Daily cycle was 12/12 hours, lights on at 6:00 a.m. All animal experiments followed the ethical guidelines for animal experiments and the Czech Republic Act No. 246/1992.
- Thy-Tau22 mice were infused for 2 months with LiPR31, with doses 5 mg/kg/day dissolved in PBS/5% Tween 80 pH 6, using SC Alzet® osmotic pumps. Control mice were infused with PBS/5% Tween 80. Alzet® osmotic pumps were subcutaneously (SC) implanted in short-term ether anesthesia, and were changed after one months of experiment.
- SC subcutaneously
- mice with ad libitum access to water were weighed, and their plasma glucose concentration was measured using Glucocard glucometer. After decapitation, the brains were dissected on ice, and cut between hemispheres. For immunohistochemical staining the half of the brain was fixed for 24 hours in 4% paraformaldehyde and dehydrated in 70% ethanol, afterward.
- the hippocampus was dissected, and lysed in cold lysis buffer (62.5 mmol.l ⁇ 1 Tris-HCl, pH 6.8 with 1% sodium deoxycholate, 1% Triton X-100, Complete, 50 mmol.l ⁇ 1 NaF, 1 mmol.l ⁇ 1 Na 3 VO 4 ), homogenized, sonicated 10 minutes and stored at ⁇ 20° C.
- the blood plasma was prepared, and stored at ⁇ 20° C.
- the escape latency was measured in 6-month-old MSG mice and their age-matched controls. Experiment was performed 5 days with 4 sessions per day. As shown in FIG. 1 , MSG mice had significantly increased escape latency compared to the control group.
- Activation of insulin signaling cascade and Tau protein phosphorylation was measured by WB analysis in hippocampi of MSG obese mice and their controls aged 2 and 6 months.
- the phosphorylation of GSK-3 ⁇ at Ser9 was detected.
- the phosphorylation was decreased in MSG mice at the age of 2 months, and furthermore significantly decreased at the age of 6 months, compared to the control mice.
- a decreased phosphorylation of Ser9 at GSK-3 ⁇ probably caused increased phosphorylation of Tau protein at epitopes Ser396 and Thr231, as shown in FIG. 2B and 2C .
- the 6-month old MSG mice were proven as suitable model for testing the effect of insulin-sensitizing compounds.
- Enhanced activation of kinases implicated in insulin signaling cascade was observed in hippocampi of 6-month-old MSG mice after 14-day intervention, either with palmitoylated analog of PrRP31, or with liraglutide, as shown in FIG. 3 .
- liraglutide treatment significantly increased phosphorylation was observed in PDK-1, Akt (Thr308), and GSK-3 ⁇ (Ser9); more pronounced phosphorylation was observed in-Akt (Thr308), and GSK-3 ⁇ (Ser9) after treatment with palmitoylated analog of PrRP31.
- Phosphorylation was detected using the method of WB. As shown in FIG. 5 , 14-day-long treatment with palmitoylated analog of PrRP31 with dichlorophenylalanin in position 31 increased phosphorylation of GSK-313 at Ser9 and subsequently led to a decreased phosphorylation of Tau protein at the epitope Thr231.
- the double immunohistochemical staining was used. As shown in FIG. 6 , the phosphorylation of Tau protein at epitopes Thr212 and Ser202/Thr205 was increased in MSG mice at the age of 6 months compared to their age-matched control, both treated with saline. Increased phosphorylation is manifested by a stronger fluorescent signal using the laser of the same intensity.
- the Tau phosphorylation is decreased in hippocampal region CA1, which is manifested by a weaker fluorescent signal, using the laser of the same intensity.
- the spatial memory was tested before and after the treatment with LiPR31 in Thy-Tau22 mice and their age-matched WT control using the Y-maze; the WT and Thy-Tau22 control group was treated with PBS/5% Tween 80.
- FIG. 7A before the experiment the Thy-Tau22 mice spent significantly less time in the newly open arm, compared to WT animals.
- the Thy-Tau22 mice spent significantly more time in the new arm compared to the PBS/Tween 80 treated group, as shown in FIG. 7B .
- Tau phosphorylation was determined in the hippocampi of Thy-Tau22 mice treated with LiPR31 and their Thy-Tau22 control using the method of WB. Compared to the control group, the attenuation of Tau phosphorylation at epitopes Thr231, Ser396 and Ser404 was observed in hippocampi of Thy-Tau22 mice treated for 2 months with LiPR31, as shown in FIG. 8A and 8B .
- AD is characterized by two pathological changes in neurons: formation of non-soluble extracellular A ⁇ plaques and hyperphosphorylation of intracellular cytoskeletal Tau protein.
- the potential neuroprotective effect of tested compound was examined in the mouse model of obesity and insulin resistance, where obesity is caused by the application of monosodium glutamate (MSG) to newborn animals.
- MSG monosodium glutamate
- Thy-Tau 22 mice a model of AD like pathology, were also used to verify neuroprotective effect of tested compound.
- New analogs of prolactin releasing peptide represent neuroprotective agents for peripheral treatment and prevention of diseases, which are Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.
- AD Alzheimer's disease
- PD Parkinson's disease
- CIND cognitive impairment no dementia
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CZ2014-364A CZ309217B6 (cs) | 2014-05-27 | 2014-05-27 | Lipidované peptidy jako neuroprotektiva |
PCT/CZ2015/000047 WO2015180698A1 (en) | 2014-05-27 | 2015-05-20 | Lipidated peptides as neuroprotective agents |
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US10899805B2 (en) | 2014-10-02 | 2021-01-26 | Paul Scherrer Institut | Human G protein alpha subunit gail with at least one mutated amino acid residue |
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ATE541921T1 (de) * | 2001-09-14 | 2012-02-15 | Stem Cell Therapeutics Inc | Prolaktin-induzierte zunahme an neuronalen stammzellen und dessen therapeutische anwendung |
WO2006030956A1 (ja) * | 2004-09-15 | 2006-03-23 | Takeda Pharmaceutical Company Limited | PrRPおよびその受容体の新規用途 |
WO2009046851A1 (en) * | 2007-09-11 | 2009-04-16 | Mondobiotech Laboratories Ag | Cgrp as a therapeutic agent |
ES2690994T3 (es) * | 2011-06-24 | 2018-11-23 | Nono Inc. | Terapia de combinación para isquemia |
CZ2012476A3 (cs) * | 2012-07-12 | 2014-01-22 | Ústav organické chemie a biochemie Akademie věd ČR, v. v. i. | Lipidované peptidy jako antiobezitika |
EP3094643B1 (en) | 2014-01-15 | 2018-10-17 | Fyziologicky ustav Akademie ved Ceske republiky, v.v.i. | Lipidated peptides for lowering blood glucose |
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US10899805B2 (en) | 2014-10-02 | 2021-01-26 | Paul Scherrer Institut | Human G protein alpha subunit gail with at least one mutated amino acid residue |
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IL248370A0 (en) | 2016-11-30 |
EP3149029B1 (en) | 2019-06-19 |
CZ309217B6 (cs) | 2022-06-01 |
CA2950416A1 (en) | 2015-12-03 |
EP3149029A1 (en) | 2017-04-05 |
US10751390B2 (en) | 2020-08-25 |
IL248370B (en) | 2019-11-28 |
US20200016240A1 (en) | 2020-01-16 |
AU2015266464B2 (en) | 2017-08-17 |
CA2950416C (en) | 2021-03-02 |
AU2015266464A1 (en) | 2016-10-27 |
CZ2014364A3 (cs) | 2015-12-16 |
WO2015180698A1 (en) | 2015-12-03 |
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