CN105916874A - Novel polypeptides - Google Patents
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Abstract
The present invention relates to an isolated polypeptide comprising (a) the amino acid sequence set forth in SEQ ID NO: 1; or (b) an amino acid sequence that is at least 95% identical to SEQ ID NO: 1, nucleic acids, vectors and host cells encoding the same, as well as therapeutic treatments based thereon.
Description
Technical field
The present invention relates to a class novel polypeptide, encode the nucleic acid of this polypeptide and include the compositions of this polypeptide, and they
Application in Therapeutic Method.
Background technology
Disturbance of carbohydrate metabolism occurs in a variety of forms, and modal disorder is acquired.Carbohydrate generation
Acquired or the Secondary cases thanked is disorderly, such as diabetic ketoacidosis, hyperosmolar coma and hypoglycemia, all affects maincenter god
Through system.Many forms of equally visible peripheral neuropathy and mutation in diabetes.Remaining of carbohydrate metabolism is disorderly
It it is disorderly rare inborn errors of metabolism (i.e. genetic defect).
The acquired disorder of carbohydrate metabolism is in U.S. and the most fairly common.At alcoholic with through insulin
Treatment diabetics in, hypoglycemia is sacred disease, particularly acute confusion decline, memory loss, disorientation, blunt with
And the common cause of stupor.Hyperinsulinemia is seldom caused by other reason, but pancreas tumor is probably its reason.Diabetes
And various neural complication is one of modal disorder in sufferer of growing up.
Diabetes are modal endocrinopathyes, it is characterized in that abnormal glucose metabolism.The Portugal relevant to this disease
Grape abnormal carbohydrate metabolism causes hyperglycemia (high blood sugar level), and ultimately results in and include that eyes, kidney, nerve and blood vessel are many
The complication of tract.The patient of persistent high blood sugar or impaired glucose tolerance is generally diagnosed as suffering from this disease, though
Right modal patient is initially present of the situation excessively urinated (polyuria) and often frequently drink water because of extreme thirst (excessive thirst).This
A little typical initial symptoms are to be caused by the osmosis of hyperglycemia.
The pathogeny of diabetes is the most relevant to dyspancreatism, particularly relevant to Langerhans beta Cell of islet.
This malfunction can result in the beta Cell of islet of insulin (a kind of glucose-regulating peptide hormone) and be destroyed, insulin
It it is then a kind of peptide hormone regulating glucose.Generally, diabetes are categorized as insulin-dependent or I type and in contrast
Non-insulin-depending type or II type.
Three kinds of principal modes of diabetes are:
-I type: caused because health can not produce insulin, its treatment is usually directed to administration of insulin.
-II type: because health can not the health status of proper use of insulin be caused, and lacking with Related Insulin
Weary.Many people finally developing into type ii diabetes can experience pre-diabetes condition for many years, and this preneoplastic state is the blood of people
Health status when sugar level is higher than normal level but the most up to be enough to be diagnosed as type ii diabetes.
-gestational diabetes: but the most never must spend the diabetes pregnancy period has anemia of pregnant woman's quilt of hyperglycemia (glucose) level
Think that there is gestational diabetes.Gestational diabetes affects about 4% in whole anemia of pregnant woman, and it is (or rare that it can continue to develop into II type
Insight is I type) diabetes.
-from the diabetes of above-mentioned form separately other form of many of classification.The example includes the something lost because of insulin secretion
Pass the congenital type ii diabetes that caused of the defect diabetes relevant to cystic fibrosis, by high dose glucocorticoid inducible
The single-gene diabetes of steroid diabetes and several form.
But, along with people are more fully understood from for such disease, the definition of above-mentioned term is also in change.Such as,
Have been found that, in some suffers from the patient of non-insulin-dependent diabetes mellitus, progression of disease is insulin-dependent, and at other
In patient, insulin dependency does not develop.
Therefore, patient is classified by the pathology often destroyed according to islets of langerhans, and the appointment of I type is currently used for referring to
Autoimmunity island pathogeny, i.e. refers to the diabetes caused by the autoimmune attack that islets of langerhans is special, and in this article
So use.Term insulin dependent diabetes mellitus (IDDM) (IDDM) refers to proceed to the type i diabetes in this stage, the most sends out
The autoimmune destruction of raw pancreatic β cell be enough to produce manifest symptom.Before term, IDDM refers to pass through biopsy or self exempt from
Autoimmune state detected by epidemic disease response analysis, beta Cell of islet is attacked by specific autoimmune in this condition, should
Attack and there is the degree causing some of them cell to be destroyed.But, in front IDDM, this destruction (if there is
Words) also do not proceed to be enough to need the degree of administration of insulin.Owing to can have a point type i diabetes early stage, wherein
Although observing manifest symptom, but some islet function still keeps (being known as " honeymooners "), thus not all I type is sugared
Urine disease is all classified as IDDM, is not that all front IDDM do not have manifest symptom.
The Metabolic complication relevant to the Developmental and Metabolic Disorder caused by insufficient insulin can affect a lot of tract.?
Common acute metabolic complication is diabetic ketoacidosis, it is characterized in that serious hyperglycemia (and produces by permeability profit
The hypovolemia that urine is caused) and produced in the metabolic acid caused by excessive free fatty release and ketoboidies
Poison.
Except the acute metabolic complication of ketoacidosis, diabetics be susceptible to suffer from a series of cause at a relatively high sickness rate and
The late complication of premature death rate.Due to glucose metabolism and the exception of lipid metabolism, atheromatosis is at patient of diabetes
Person more extensively and earlier occurs than general groups.This vascular pathological especially can cause coronary artery disease, apoplexy,
And the peripheral blood vessel with gangrene.Retinopathy is the another kind of vascular complication of diabetes.Diabetic retinopathy
Being to cause blind main cause, it causes by increasing the permeability of retinal capillary, and this permeability increase can
Progress to blocking, hemorrhage, form aneurysm and be known as the neovascularization of proliferating retinopathy.
As it has been described above, Cautious control blood glucose is relevant to the late complication improving type i diabetes, this shows to retain or recover
The function of β cell can be reduced or eliminated most of pathologic complication of this disease.
The genetic disorder of carbohydrate metabolism is the rarest.Report acetone acid in little patient's (2-6 example)
The major defect of dehydrogenase (PDH) complex and the most pentosuric optimum chemical abnormality.
Hypoglycemia, diabetic ketoacidosis and hyperosmolar coma are all possible to fatal, but likely cure
Disease.
In WO 2011/016026, inventors have discovered that the secretory protein of various new, i.e. PRT5, PRT6,
PRT7 and PRT8.Especially, it has been shown that PRT8 can significantly decrease the glucose level in blood.
But, inventor is it has now surprisingly been found that the PRT8 peptide of shortening, i.e. sbPRT8 has than complete length
The biological activity that PRT8 peptide improves, and can significantly more reduce blood sugar level, and other PRT8 fragment is the most aobvious
Any essence activity is shown.
Therefore, it is an object of the present invention to provide the polypeptide of the activity compared with PRT8 with improvement, and coding should
The nucleic acid of polypeptide, carrier and cell.
It is a further object of the present invention to provide sbPRT8 for treatment and glucose in blood excess (i.e. hyperglycemia) phase
The disease closed or the method for disorder and purposes.
These and other purposes of the present invention and its purpose will become apparent from along with following description.
Summary of the invention
It is an object of the invention to provide the polypeptide of a kind of separation, comprising: the aminoacid that (a) is as shown in SEQ ID NO:1
Sequence；Or (b) has the aminoacid sequence of at least 95% similarity with SEQ ID NO:1；Wherein, described polypeptide can reduce
Glucose level in blood.In a detailed description of the invention, the polypeptide of separation is by the aminoacid as shown in SEQ ID NO:1
Sequence forms.In another detailed description of the invention, polypeptide is modified by acetyl group at its N-end, passes through amide groups at its C-end
Group modifies.
Invention further provides a kind of pharmaceutical composition, it includes the polypeptide that separates as defined above and at least
A kind of pharmaceutically acceptable carrier, excipient or diluent.
Present invention also offers a kind of is that the aforementioned polypeptides of effective dose is in terms of reducing experimenter's blood sugar level in treatment
Purposes.In some detailed description of the invention, described experimenter suffers from the disease relevant to hyperglycemia or disorder, this disease
Sick or disorder can be selected from, but not limited to: type 1 diabetes, type 2 diabetes mellitus, metabolism syndrome, obesity, nephropathy, retinopathy,
Cardiovascular disease, gland dysfunction, pancreatic disease, sepsis, intracranial disease and postoperative pressure.
It is sweet at reduction experimenter's blood plasma that the present invention still further provides a kind of aforementioned polypeptides in treatment for effective dose
The purposes of oil three esters (TG) horizontal aspect.
Invention further provides a kind of aforementioned polypeptides sugar in reducing experimenter's blood for effective dose in treatment
Change the purposes of hemoglobin (HbA1c) horizontal aspect.
The nucleic acid molecules that invention further provides the separation of coded polypeptide, the expression vector including this nucleic acid molecules,
And include the host cell of this expression vector；Wherein, this polypeptide includes: (a) aminoacid sequence as shown in SEQ ID NO:1
Row；Or (b) has the aminoacid sequence of at least 95% similarity with SEQ ID NO:1.
Accompanying drawing explanation
The effect of Figure 1A-1B:sbPRT8 C57Bl/6 mice to processing through streptozotocin (streptozotocyn, STZ)
Really；
Figure 1A: this illustrates has injected the C57Bl/6 mice of STZ (by the dosage lumbar injection 4 days of 50mg/kg) and using
PRT8 or sbPRT8 treats 5 weeks and presses the glucose level after dosage lumbar injection glucose (IPGTT) of 1mg/kg；
Legend :-◆-PRT8 100 every mice of μ g/；-▲-sbPRT8 20 every mice of μ g/；-■-sbPRT8 100μ
G/ every mice；Glucose=glucose；Time after Time=injectable dextrose monohydrate；
Figure 1B: this illustrates has injected the C57Bl/6 mice of STZ (by the dosage lumbar injection 4 days of 50mg/kg) and using
PRT8 or sbPRT8 treats 4 weeks and presses the glucose level after dosage lumbar injection glucose (IPGTT) of 1mg/kg；
Legend :-▲-PRT8 100 every mice of μ g/；-■-sbPRT8 100 every mice of μ g/；-◆-SbPRT8 300
Every mice of μ g/.
Detailed description of the invention
WO 2011/016026 discloses the novel protein of named PRT5, PRT6, PRT7 and PRT8.Especially at pancreas
With testis is found that PRT8, and in liver, have also discovered PRT8 equally.Especially, have shown that PRT8 can significantly reduce
Glucose level in blood.
In the present invention, inventor is surprisingly found that the PRT8 peptide shortened, i.e. sbPRT8 has than complete length
The biological activity that PRT8 peptide improves, and can significantly more reduce blood sugar level.
Therefore, a first aspect of the present invention provides the polypeptide of a kind of separation, and it includes the ammonia as shown in SEQ ID NO:1
Base acid sequence, and its homologue and derivant；Wherein, the glucose level that described many Toplink reduce in blood (i.e. reduces
Concentration of glucose in blood).
Term used herein " polypeptide " refers to polypeptide or albumen.Polypeptide can be synthesized by gene engineering method and
, and express in host cell, or be synthesized into by other appropriate means.Unless otherwise indicated, polypeptide is generally by natural
The l-amino acid composition existed.
In certain embodiments, the polypeptide of the present invention is modified at its C-end and/or N-end.A specific embodiment
In, peptide is modified to as follows: acetyl group-(peptide sequence)-amide.In some other specific embodiment, the polypeptide quilt of the present invention
It is modified to that there is one or more group selected from biotin group, fluorophor or cysteine residues.
About adorned polypeptide, fragment and its homologue and derivant, in conjunction with the present invention, it should be understood that it keeps such as
The biological activity of the polypeptide shown in SEQ ID NO:1.In order to determine whether polypeptide keeps the most similar to unmodified molecule
Biological activity, can perform one or more measure, the most external, internal or clinical experiment, wherein by adorned polypeptide
Compare with corresponding unmodified polypeptide, the polypeptide of this unmodified and adorned polypeptide parallel assay or carry out reality individually
Test.
Adorned polypeptide or variant polypeptide can include that at least two, three or more sbPRT8 copies are many
Peptide, these copies are separated by amino acid spacer region alternatively.Adorned polypeptide can also is that with SEQ ID NO:1 have to
Few 70%, be preferably at least 80%, more elect at least 90%, particular at least 95% mutually unison polypeptide as.
Present invention also offers the polypeptide derived from sbPRT8, such as by preservative replacement by wherein one or more
Aminoacid replaces with other amino acid whose modified polypeptide.As used in this article, " preservative replacement
(conservative substitution) " refer to that the aminoacid in a classification is replaced by same category of aminoacid, its
In class be by common physical chemistry amino acid side chain character and the high displacement frequency in the homologous protein of natural discovery
Rate defines.The most divided amino acid side chain of 6 kinds of general classes, including: classification I (Cys)；Classification II (Ser, Thr,
Pro、Ala、Gly)；Classification III (Asn, Asp, Gln, Glu)；Classification IV (His, Arg, Lys)；Classification V (Ile, Leu, Val,
Met)；With classification VI (Phe, Tyr, Trp).Such as, Asp is replaced into the another kind of residue of classification III, such as Asn, Gln or Glu
Displacement be preservative replacement.
In one embodiment, aminoacid sequence only has a displacement；In another embodiment, there are two displacements；?
In another embodiment, there are three displacements.The maximum quantity of displacement should be less than following aminoacid quantity: in the sequence do not replaced
Row retain at least 70%, be desired at least 80%, be preferably at least 90%, the aminoacid of most preferably at least 95%.One
In individual specific embodiment, including less than 3, sometimes less than 6 displacements by the amino acid residue of other aminoacid replacement
It it is preservative replacement.In another embodiment, one or more aminoacid can be by D-aminoacid, the most corresponding D-amino
Acid is replaced.In a specific embodiment, all of aminoacid is all D-aminoacid.
Preferably displacement is the change expecting not change the secondary structure of polypeptide, the i.e. change of conservative.Following table shows
The aminoacid (right side) can replaced with Original amino (left side).
According to amino acid whose basic feature, such as electric charge, side chain size etc., aminoacid can also be grouped.Following table shows
Show the group of Similar amino acids.Preferably replace the aminoacid occurred from a group to replace with the aminoacid in same group
Change, as follows:
1, little residue aliphatic, nonpolar: Ala, Ser, Thr, Pro, Gly；
2, polarity, negative charge residue and amide thereof: Asp, Asn, Glu, Gln；
3, polarity, positive charge residue: His, Arg, Lys；
4, big residue aliphatic, nonpolar: Met, Leu, Ile, Val, Cys；
5, the big residue of aromatic series: Phe, Tyr, Trp.
As described in detail by hereinafter, hereinbefore detailed preferred conservative amino acid displacement is desired for substantially
Keep or increase function or the activity of albumen of the present invention.Certainly, wherein obtained polypeptide maintains any of its original function
Amino acid replacement, add or delete and be regarded as within the scope of the invention.Such as, preservative replacement is the wherein present invention
Polypeptide is still identified the displacement that the antibody of wild type peptide is identified.
The polypeptide of the present invention can pass through conventional chemical processes, such as solid phase synthesis (using such as FMOC and BOC technology)
Produce with liquid phase synthesis.These albumen or polypeptide can also be in bacterial cell, insect cell or other internal eukaryotic transcription systems
System produces.After generation, polypeptide is purified from the cell producing them.The purification of polypeptide and separation method are this areas
Known to the skilled person.Advantageously, polypeptide can be as having the second albumen (such as glutathione-S-transferase (GST) or similar
Thing) or the fusions of sequence label (such as histidine-tagged (His-label) sequence) and produce.Fusions or label protein should
With simplifying purifying procedure.
The polypeptide of the present invention can also synthesize in cell free system, such as, use cell extract or ribosome.
The polypeptide of the present invention can be further embellished, to improve its function, affinity or stability.For example, it is possible to make
By cyclisation to give the higher stability of polypeptide and/or the performance of major tuneup.Have been developed for many different cyclisation
Method, including side chain cyclisation and Backbone cyclization, these methods are existing in the prior art sufficiently to be recorded.A kind of concrete cyclisation
The Stabilization of the alpha-helix of the facultative molecule that method relates to the para-orientation amino acid derivativges by use phenyl ring and realizes.
Another kind of concrete cyclization method is Backbone cyclization.Another kind can also be used to relate to the cyclization method that skeleton is connected with side chain.
But, according to the present invention, the polypeptide of the present invention can be at its N-end and/or C-end with multiple identical or different having
Machine group extends, this organic group is not naturally-occurring or the aminoacid of synthesis.As an embodiment of this extension, many
Peptide can extend at its N-end and/or C-end with N-acetyl group.
In order to improve polypeptide structure, the polypeptide of the present invention can be by its N-end and dodecyl-cysteine (LC) residue
Connect and/or be connected with cysteine (C) residue by its C-end, or be suitable to polypeptide and be used for what immune adjuvant was connected
Other residue connects.
On the other hand, the invention provides the nucleic acid of a kind of separation, its polypeptide as shown in SEQ ID NO:1 of coding and
Derivant and analog.
As used in this article, term " nucleic acid molecules " is intended to include DNA molecular (such as cDNA), RNA molecule (example
Such as mRNA) and DNA or the RNA analog of use nucleotide analog generation.Nucleic acid molecules can be strand or double-strand, but
It is preferably double-stranded DNA.
Term " nucleic acid molecules of separation " is intended to include being isolatable from the nucleic acid molecules of other nucleic acid molecules, and when by restructuring
When technology produces, it there is no other cellular material or culture medium, or when chemosynthesis, it there is no chemistry
Presoma or other chemicals.
Derivant in the scope of the invention also includes polynucleotide derivant.Polynucleotide derivant or nucleic acid derivative are not
It is same as in described in nucleotide sequence or known sequence.Such as, the feature of polynucleotide derivant can be one or many
The displacement of individual nucleotide, insert or delete.
The nucleic acid molecules of the present invention, i.e. has the nucleic acid molecules of the nucleotide sequence of coding sbPRT8, can be by using
Standard molecular biological technique and sequence information provided in this article and generate.
Another further aspect, the invention provides a kind of carrier, and it includes the nucleic acid molecules separated, and this nucleic acid molecules can encode such as
Polypeptide shown in SEQ ID NO:1 or its functional derivatives or the like.In an embodiment of this carrier, described
Nucleic acid molecules may be operably coupled to promoter.In another embodiment, described carrier is expression vector.
As used in this article, term " carrier " is intended to include such nucleic acid molecules, and it can be by another nucleic acid
It is transported to the position that this nucleic acid molecules has connected.The feature of carrier can be one or a small amount of multiple restriction endonuclease
Site, these DNA sequence in site can cut in a predetermined manner and not make carrier lose main biological function,
And can connect into DNA fragmentation in site, so that it is replicated and is cloned.Carrier can comprise further be suitable for for
Identify the label of the cell with vector.A type of carrier is " plasmid ", and it refers to that extra DNA fragmentation can connect
It is connected to circular double-stranded DNA ring therein.Another type of carrier is viral vector, and the most extra DNA fragmentation can connect
To viral genome.Some carrier independently can replicate in the host cell that they are introduced into (such as to be had antibacterial to replicate
The bacteria carrier of point and episomal mammalian vectors).Other carrier (such as non-free type mammalian vector) by introduction into
Host cell is bound to the genome of host cell, thus replicates along with host genome.Additionally, some carrier can
Guide the expression of the gene being operably connected with them.In this article such carrier is referred to as " expression vector ".General and
Speech, the expression vector used in recombinant DNA technology is typically the form with plasmid.In this manual, due to plasmid it is
Most generally used carrier format, thus " plasmid " and " carrier " can the most alternatively use.But, the invention is intended to include
The expression vector of other form of equal function is provided, such as viral vector (as replication defect type retrovirus, adenovirus and
Adeno-associated virus).
Term " is operably connected " and is meant that the most functional link between molecule because the activity of a kind of molecule or
The change of state is affected by activity or the state of another kind of molecule.As regulation sequence and encoding target polypeptide or the DNA of albumen
During functional nucleotide sequence association, nucleotide sequence is " being operably connected ".Such as, if promoter nucleotide sequence controls to compile
The DNA sequence of code target protein is transcribed, then promoter nucleotide sequence operationally connects with the DNA sequence of encoding target polypeptide
Connect.Typically, two polypeptide being operably connected are connected by covalent peptide bonds.
Another aspect, the invention provides a kind of cell including above-mentioned carrier, and this carrier includes encoding such as SEQ ID
The nucleic acid molecules of the separation of the polypeptide shown in NO:1 and derivant or the like thereof.In a specific embodiment, this cell is
Select the host in the group that free plant cell, insect cell, fungal cell, bacterial cell or mammalian cell formed thin
Born of the same parents.
Term " host cell " and " recombinant host cell " can the most alternatively use in this article." host cell " wraps
Include any educable cell can modified by introducing foreign DNA.Preferably, host cell is wherein transcription regulation protein
Can stably express in vain, posttranscriptional modification, location to suitable subcellular fraction room participate in suitably transcribing the cell of tissue.Detection
The selection of signal equally has influence on the selection of Suitable host cells.Such as, as it has been described above, reporter construct can be based on
The genetic transcription of response NlmRⅠ activate or suppression and the selectable characteristic maybe can screened is provided；In order to reach
Good selection or screening, it will be considered that the Phenotype of host cell.Should be appreciated that such term not merely refers to concrete tested
Person's cell, also includes the offspring of this cell or possible offspring.Because being likely to be due to sudden change or environment in offspring subsequently
Impact and occur some to change, such offspring in fact may with parental cell differing, but they are still included in
In the range of term as used herein.
The host cell of the present invention includes prokaryotic cell and eukaryotic cell.Prokaryote includes Gram-negative or gram
Positive organisms, such as escherichia coli or bacillus (Bacilli).Be suitable to such as include for the prokaryotic host cell converted: large intestine
Multiple in bacillus, Bacillus subtillis, Salmonella typhimurium, and Rhodopseudomonas, streptomyces and staphylococcus
Other kind.Eukaryotic cell includes but not limited to: yeast cells, plant cell, fungal cell, insect cell (such as baculovirus),
Mammalian cell and the cell of parasite (such as trypanosoma).
As used in this article, term " yeast " not only includes the yeast in strict classification meaning, the most unicellular
Biology, also includes yeastlike many cells fungus or filamentous fungi.Exemplary kind includes Kluyveromyces lactis, foxtail millet wine fragmentation
Yeast and Ustilaqo maydis, wherein saccharomyces cerevisiae is preferred.Other yeast that can use in the practice of the present invention is
Neurospora crassa (Neurospora crassa), aspergillus niger, aspergillus nidulans, Pichia sp., candida tropicalis and the multiform Chinese are inferior
Yeast (Hansenula polymorpha).
Mammalian host cell culture systems includes the cell line having built up, and such as HeLa cell, COS cell, L are thin
Born of the same parents, 3T3 cell, Chinese hamster ovary (CHO) cell, embryonic stem cell, etc..
On the other hand, present invention also offers the compositions of a kind of polypeptide sbPRT8 including and separating；Wherein, this polypeptide bag
Include sequence or derivatives thereof shown in SEQ ID NO:1 as above or the like.
In a specific embodiment, compositions provided by the present invention may further include pharmaceutically acceptable assistant
Agent, carrier, excipient or diluent.
Term " pharmaceutically acceptable carrier " meaning is any one inertia do not reacted with active component, nontoxic material
Material.It is sometimes based upon desired dosage form and selects carrier.Sometimes carrier can also have promotion by active component deliver or ooze
Thoroughly to the effect of destination organization, for promoting the stability of medicine, slowing down clearance rate, give On The Drug Release character, reduce the not phase
The side effect etc. hoped.Carrier can also be the material (such as preservative) of stabilization formulations, for providing edible flavour for preparation
Deng.Carrier can be normally used any one in those, and only by chemical-physical factor, such as dissolubility and shortage
With the reactivity of antibody of the present invention, and route of administration limit.Carrier can include additive, coloring agent, diluent, buffering
Liquid, disintegrating agent, wetting agent, preservative, flavoring agent and pharmaceutically-compatible carrier.Additionally, carrier can be adjuvant, this adjuvant
It is defined as affecting in a predictive manner the material of active component effect.The exemplary of carrier includes: (a) liquid solution, its
The active substance of middle effective dose is dissolved in the diluent of such as water, saline, natural juice, alcohol, syrup etc.；B () capsule (such as comprises
Common duricrust or soft-shelled gelatin type such as surfactant, lubricant and inert filler), tablet, lozenge (wherein active matter
Matter is in flavouring agent, in sucrose and Radix Acaciae senegalis (acacia) or tragacanth (tragacanth)；Or active substance exists
In inert base, in gel and glycerol) and lozenge, each of which comprises the activity examination as solid or granule of scheduled volume
Agent；(c) powder；(d) suspension in suitable liquid；(e) suitably emulsion；(f) Liposomal formulation；And other.
In another specific embodiment, the compositions of the present invention can also selectively farther include the activity added
Agent, such as but not limited to antibiotic, cytokine, lymphokine, somatomedin, hormone, antioxidant and vitamin etc..
On the other hand, present invention also offers polypeptide sbPRT8 purposes in preparing medicine, this medicine for treatment with
Disease that hyperglycemia is relevant or disorder, especially choosing free type 1 diabetes, type 2 diabetes mellitus, metabolism syndrome, obesity, kidney
Disease, retinopathy, cardiovascular disease, gland dysfunction, pancreatic disease, sepsis, intracranial disease and postoperative pressure are formed
Disease in group or disorder.
Term as referred to herein " effective dose " meaning is the necessary amount of result realizing being selected, and it relates at present
The disorderly necessary sbPRT8 for the treatment of or the amount of its reactive derivative biologically.
The described effective dose in treatment or effective dose depend on the order of severity of the morbid state needing treatment with anti-
Ying Xing, continues one hour to several hours its course for the treatment of, one day to several days, or until recovery from illness or morbid state have been alleviated.Commonly
Technical staff can readily determine that optimum dosage, quantitative dosing method and repetitive rate.Optimum dosage can foundation
Each of present invention polypeptide or albumen or the relative effectivenes of the compositions that comprises it and change, and be typically based on EC50Estimate,
This is found in the external and internal the most effective of animal model.Those of ordinary skill in the art can be easily residual based on measuring
Stay time and concentration to estimate to be administered repetitive rate, and adjust used polypeptide or albumen.
Term as used herein " is treated " or the meaning of " process " is to improve the disease of the patient suffering from disease or disorder
The clinical instruction of one or more of activity." process " and refer to therapeutic treatment.
" patient " or " experimenters of needs " means that its disorder of expectation treatment or disease are described disorderly or disease to overcome
Any mammal, particularly human experimenter.
Generally, " effective dose in treatment " again by the order of severity of disease and combine preventative or therapeutic purpose,
The integrated status of route of administration and patient (age, sex, body weight and other Consideration known to the doctor in charge) and determine.
Can use multiple medication that sbPRT8 described in the invention is delivered to the experimenter needed.This polypeptide
Or include that the compositions of this polypeptide can pass through vein (i.v.) injection, intramuscular (i.m.) injection, intraperitoneal (i.p.) injection, office
Portion's injection or other suitable approach any of being found by those skilled in the art and deliver.In order to effectively treat, the present invention
Polypeptide or albumen should be so that they can the most stable mode be prepared after administration.
As used in this article, term " disorderly " refers to the situation of wherein normal function multilated." disease " is to cause
Make affected people or other people's discomfort, dysfunction or the health of worries that contact with this people or spiritual any exception
Situation.Sometimes, this term be widely used as including injury, congenital malformation, deformity, syndrome, symptom, irregularities,
Chronic or the permanent healthy defect that the atypia of 26S Proteasome Structure and Function changes and caused by disease.
Term " disease ", " disorderly ", " situation " and " sick " can the most alternatively use in this article.
When censuring experimenter herein, this experimenter can be the mankind or inhuman mammal.Inhuman
Mammal includes but not limited to cattle, horse, Canis familiaris L., cat, mice, rat, Cavia porcellus etc..Generally, experimenter is the mankind, especially suffers from
Person or the people of health.
As disclosed and described in, it should be understood that the invention is not restricted to specific embodiment disclosed herein, method step and
Material, because these method steps and material can some changes.It will also be appreciated that owing to the scope of the present invention will be only by appended
Claim and its equivalent are any limitation as, thus term as used herein is only used for describing the purpose of specific embodiments
And be unrestrictedly intended to.
Must be noted that unless context is additionally expressly noted that, such as institute in this specification and claims thereof
Using, " " and " being somebody's turn to do " of singulative includes the referent of plural number.
In this specification and its appended claim, unless the context requires otherwise, term " includes " and becomes
Entirety that change form such as " comprising ", " containing " is understood to mean to include determining or step or the overall or set of step, but
It is not excluded for other overall or step any or the overall or set of step.
As used in this article, " disease relevant to hyperglycemia or disorder " refer to wherein excess glucose exist
The disease circulated in blood plasma or disorder.This is typically glucose level and is higher than 11.1mmol/l (200mg/dl), but until even
Much higher value, such as 15-20mmol/l (～250-300mg/dl), symptom just starts to become to discover.According to America Diabetes
Association's guide, is thought of as blood glucose too high, and is higher than when the glucose level of experimenter is continuously in the range of 100 to 126
126mg/dl or 7mmol/l is then typically considered to suffer from diabetes, and level can produce more than 7mmol/l (125mg/dl) for a long time
Organ injury.The disease relevant to hyperglycemia or disorder include: diabetes (1 type and 2 types), nephropathy, retinopathy, cardiovascular
Disease (such as apoplexy, myocardial infarction), gland dysfunction (such as thyroid, adrenal gland or hypophysis), pancreatic disease, sepsis, intracranial
Disease (such as encephalitis, cerebroma, cerebral hemorrhage, meningitis).Prolonged major operation can temporarily increase glucose level.?
Near result is it is also shown that under non-fasting state, in the way of not relying on plasma insulin or free fatty acid levels, acute
Hyperglycemia increases plasma triglyceride (TG) by stimulating the TG secretions of liver.
As used in this article, " glycolated hemoglobin " (be also called glycated hemoglobin, HbA1c, A1C, Hb1c or
HbA1c) being the hemoglobin of this form, it is the most determined determines the denseest in long term time of plasma glucose
Degree.The nonenzymatic glycosylation approach that it is exposed to plasma glucose by hemoglobin is formed.The glucose of normal level is just producing
The glycolated hemoglobin of constant.Along with the increase (hyperglycemia) of plasma glucose average magnitude, glycolated hemoglobin part is with can
The mode of prediction increases.In diabetes, the glycolated hemoglobin of higher amount with cardiovascular disease, nephropathy and retinopathy
It is associated.
Following example represent the representative art that inventor is used when implementing aspect of the present invention.Though should be appreciated that
So these technology are the examples for implementing the preferred embodiments of the invention, but those skilled in the art will according to the disclosure
Recognize and can carry out many amendments under conditions of without departing from desired extent of the present invention.
Unless defined, whole technology used herein and scientific terminology have and the technical field of the invention
Those of ordinary skill be generally understood that identical implication.
Comparative example 1
Compared with using with PRT8, sbPRT8 uses the C57Bl/6 mouse glucose water processed through streptozotocin (STZ)
Flat effect
In following experiment, have employed and have acetyl group at its N-end block and have amide group at its C-end block
(NH2) sbPRT8 peptide.The effect to glucose level is used checking sbPRT8 in the mice that streptozotocin (STZ) processes
Really, and with PRT8, it is used played effect to compare.Those skilled in the art are known, and STZ is a kind of dynamic to suckling
The pancreatic beta cell producing insulin in thing has the compound of special toxicity, and it is medically for treating langerhans islands
Some cancer, and for producing the animal model of type 1 diabetes and type 2 diabetes mellitus in medical research.
Embodiment 1:
C57Bl/6 male mice is buied from the Harlan Laboratories Ltd. being positioned at Jerusalem Road,Israel.Warp
After crossing the rest of 7 days, by the dosage of 50mg/kg, mice IP is injected STZ 4 days.After 5 days of STZ injection, mice is entered
Row is following to be processed:
Every mice of-A group (comparison)-PRT8100 μ g/ (comparison)
-B group (process)-sbPRT820 every mice of μ g/ (processes 1)
-C group (comparison)-sbPRT8100 every mice of μ g/ (processes 2)
After the process of 5 weeks, only making mice hungry 12 hours, its IP is injected Portugal by the dosage then pressing 1mg/kg
Grape sugar juice (IPGTT).After glucose injection the 0th, 15,30,60,90 and 120 minutes, use Accucheck blood glucose
Detector (Roche) measures the glucose level in mouse blood.
Embodiment 2:
C57Bl/6 male mice is buied from the Harlan Laboratories Ltd. being positioned at Jerusalem Road,Israel.Warp
After crossing the rest of 7 days, by the dosage of 50mg/kg, mice IP is injected STZ 4 days.After 5 days of STZ injection, mice is entered
Row is following to be processed:
Every mice of-A group (comparison)-PRT8100 μ g/ (comparison)
-B group (process)-sbPRT8100 every mice of μ g/ (processes 1)
-C group (comparison)-sbPRT8300 every mice of μ g/ (processes 2)
After the process of 4 weeks, only making mice hungry 12 hours, its IP is injected Portugal by the dosage then pressing 1mg/kg
Grape sugar juice (IPGTT).After glucose injection the 0th, 15,30,60,90 and 120 minutes, use Accucheck blood glucose
Detector (Roche) measures the glucose level in mouse blood.
Result is shown in Figure 1A-1B.In all process, glucose level after injection within the 30th minute, reach peak value.
Although injection PRT8 makes the blood sugar level of mice significantly reduce, but injection sbPRT8 shows in terms of reducing blood sugar level
Astonishing and the improvement of highly significant.These results clearly demonstrate that (sbPRT8, it is the C-of PRT8 to SEQ ID NO:1 peptide
End fragment), there is the glucose lowering activity improved than the PRT8 peptide of complete length.Use two kinds of other PRT8 fragments, i.e.
SEQ ID NO:2 (PRT8N-ter) and SEQ ID NO:3 (PRT8C-ter) has carried out similar experiment, with employing sbPRT8 institute
The result obtained is contrary, does not observe that significant blood glucose reduces.
From the foregoing it can be that in terms of glucose metabolism regulation and blood sugar level reduction, with the PRT8 peptide of complete length
Comparing, small peptide sbPRT8 shows and is markedly improved potentiality.Therefore, sbPRT8 treat the disease relevant to hyperglycemia or
Disorderly aspect can be significant.It addition, sbPRT8 may be used for reducing the blood level (HbA1c of glycolated hemoglobin
Level) and reduce plasma triglyceride (TG) level, because both levels are all closely-related with blood sugar concentration.
All of the above is provided to describe and being intended to indicate that rather than limit the present invention by any way of embodiment.
Claims (11)
1. the polypeptide separated, comprising: the aminoacid sequence that (a) is as shown in SEQ ID NO:1；Or (b) and SEQ ID
NO:1 has the aminoacid sequence of the similarity of at least 95%；Wherein, described many Toplink reduce the concentration of glucose in blood.
2. the polypeptide separated as claimed in claim 1, it is made up of the aminoacid sequence as shown in SEQ ID NO:1.
3. the polypeptide separated as claimed in claim 1 or 2, wherein, described polypeptide is modified by acetyl group at its N-end,
Modified by amide group at its C-end.
4. a pharmaceutical composition, it polypeptide including separation as described in one of claims 1 to 3 and at least one medicine
Acceptable carrier, excipient or diluent on.
5. polypeptide or the pharmaceutical composition as claimed in claim 4 of the separation as described in one of claims 1 to 3 exists
Treat the purposes in terms of the disease relevant to hyperglycemia or disorder；Wherein, described disease or disorderly selected from such as next group: 1
Patients with type Ⅰ DM, type 2 diabetes mellitus, metabolism syndrome, obesity, nephropathy, retinopathy, cardiovascular disease, gland dysfunction, pancreas
Disease, sepsis, intracranial disease and postoperative pressure.
6. polypeptide or the pharmaceutical composition as claimed in claim 4 of the separation as described in one of claims 1 to 3 exists
Reduce the purposes in terms of blood sugar level.
7. polypeptide or the pharmaceutical composition as claimed in claim 4 of the separation as described in one of claims 1 to 3 exists
Reduce the purposes of triglyceride (TG) horizontal aspect in blood plasma.
8. polypeptide or the pharmaceutical composition as claimed in claim 4 of the separation as described in one of claims 1 to 3 exists
Reduce the purposes of glycolated hemoglobin (HbA1c) horizontal aspect in blood.
9. coding nucleic acid molecules of the separation of polypeptide as described in one of claims 1 to 3.
10. the expression vector including nucleic acid molecules as claimed in claim 9.
11. 1 kinds of host cells including expression vector as claimed in claim 10.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14/146,237 | 2014-01-02 | ||
| US14/146,237 US9296786B2 (en) | 2009-08-02 | 2014-01-02 | Shortened secreted polypeptides |
| PCT/IL2014/051136 WO2015101984A1 (en) | 2014-01-02 | 2014-12-30 | Novel polypeptides |
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| Publication Number | Publication Date |
|---|---|
| CN105916874A true CN105916874A (en) | 2016-08-31 |
Family
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| CN201480072200.6A Pending CN105916874A (en) | 2014-01-02 | 2014-12-30 | Novel polypeptides |
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| EP (1) | EP3089988A4 (en) |
| JP (1) | JP2017502675A (en) |
| CN (1) | CN105916874A (en) |
| AU (1) | AU2014374945A1 (en) |
| CA (1) | CA2935624A1 (en) |
| IL (1) | IL246533A0 (en) |
| SG (1) | SG11201605354WA (en) |
| WO (1) | WO2015101984A1 (en) |
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| CN113943344B (en) * | 2021-09-30 | 2024-03-15 | 吉林农业大学 | High-activity memory improvement derivative peptide and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914150A (en) * | 2009-03-12 | 2010-12-15 | 刘建宁 | Polypeptide and use thereof in medicament preparation |
| CN102596247A (en) * | 2009-08-02 | 2012-07-18 | 两合生物科技公司 | Novel proteins |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US9296786B2 (en) * | 2009-08-02 | 2016-03-29 | Two To Biotech Ltd. | Shortened secreted polypeptides |
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2014
- 2014-12-30 JP JP2016544556A patent/JP2017502675A/en active Pending
- 2014-12-30 WO PCT/IL2014/051136 patent/WO2015101984A1/en active Application Filing
- 2014-12-30 AU AU2014374945A patent/AU2014374945A1/en not_active Abandoned
- 2014-12-30 SG SG11201605354WA patent/SG11201605354WA/en unknown
- 2014-12-30 CA CA2935624A patent/CA2935624A1/en not_active Abandoned
- 2014-12-30 CN CN201480072200.6A patent/CN105916874A/en active Pending
- 2014-12-30 EP EP14876711.4A patent/EP3089988A4/en not_active Withdrawn
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914150A (en) * | 2009-03-12 | 2010-12-15 | 刘建宁 | Polypeptide and use thereof in medicament preparation |
| CN102596247A (en) * | 2009-08-02 | 2012-07-18 | 两合生物科技公司 | Novel proteins |
Non-Patent Citations (1)
| Title |
|---|
| HAN W 等: "Molecular cloning and characterization of chemokine-like factor 1 (CKLF1), a novel human cytokine with unique structure and potential chemotactic activity", 《THE BIOCHEMICAL JOURNAL》 * |
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| Publication number | Publication date |
|---|---|
| JP2017502675A (en) | 2017-01-26 |
| AU2014374945A1 (en) | 2016-07-21 |
| WO2015101984A1 (en) | 2015-07-09 |
| CA2935624A1 (en) | 2015-07-09 |
| SG11201605354WA (en) | 2016-07-28 |
| IL246533A0 (en) | 2016-08-31 |
| EP3089988A1 (en) | 2016-11-09 |
| EP3089988A4 (en) | 2017-08-02 |
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