CN106632603B - One group of peptide and its pharmaceutical composition and application - Google Patents
One group of peptide and its pharmaceutical composition and application Download PDFInfo
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- CN106632603B CN106632603B CN201611128087.6A CN201611128087A CN106632603B CN 106632603 B CN106632603 B CN 106632603B CN 201611128087 A CN201611128087 A CN 201611128087A CN 106632603 B CN106632603 B CN 106632603B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The present invention provides one group of peptide and its pharmaceutical composition and application, wherein peptide is the amino acid sequence or their pharmaceutically acceptable salt with analgesic activity as shown in sequence table.Two cysteines of the head end and end that provide peptide form ring.The present invention is by comparing a variety of polypeptide sequences containing cysteine knot (ICK) such as GsMTx-4, GsMTX-2, and detected by the behaviouristics to rat pain model, the pharmacophore (structural domain) that analgesic activity is played in GsMTx-4 polypeptide has been determined.
Description
Technical field
The invention belongs to biomedicine technical fields, are related to one group of new type of peptides, in particular to that applies in medicine has
The peptide of analgesic activity or their pharmaceutically acceptable salt.Moreover, it relates to which this group of peptide is used to prepare pharmaceutical composition
Object.
Background technique
2000, the U.S. about state university Frederick doctor Sachs was from a kind of Chilean tarantula (Chilean
Tarantula polypeptide GsMTx-4 (Sachs F, et a., J Gen Physiol.115, Po583-) are successfully separated out in venom
598,2000), it is reported that, this is the polypeptide that a kind of pair of mechanosensitive ion channels have Specific Inhibitory Effect.
GsMTx-4 is found the congestive heart failure that can be used for preventing being generated by cellular swelling, especially at positions such as lung, liver, legs
(Sachs F.et al.,JGP 2000).Also report points out that GsMTx-4 can inhibit rabbit auricular fibrillation without to heart
Other functions have an impact, thus it can be used for treating heart disease (Sachs, F.et al., Nature 409, pp 35~
36,2001；Hamill, 0.P., Martinac, B., Physiol.Rev.81, pp 685~740,2001.).In addition, GsMTx-
4 may can treat brain tumor (Sachs, F.et al., J.Gen.Physiol.115, pp 583~598,2000).
United States Patent (USP) 12153942 (16.07.2009), 10550102 (12.10.2006), 04723309
(28.12.2005) can inhibit low molecular weight polypeptide (the Low-molecular weight peptides of ion channel activity
inhibiting ion channel activity).1 609 861 B1 (Pub.No.:WO/2004/ of European patent EP
085647) inhibit the low molecular weight polypeptide (English: Low-molecular weight peptides of ion channel activity
inhibiting ion channel activity；Japanese: イ オ Application チ ャ ネ Le activity The encumbers The Ru low molecule ペ プ
チ De) above content in Japan also applied for patent.It is that same group of researcher and Japanese firm jointly apply.The invention mentions
Supply a series of from the short chain polypeptides come out derived from overall length GsMTx-4, the short chain polypeptides of these low molecular weights are found can be with
Specifically inhibit the activity of the dirty middle big conductance potassium-channel SAKca of mechano-sensitive of heart.
Polypeptide GsMTx-4 mentioned above contains 34 amino acid, molecular weight 1,094Da, wherein there is 6 half Guangs
Histidine residue forms the characteristic of three pairs of cysteine knots (ICK:Inhibitor cysteine Knot motif) structure
(Robert.et al., J.Biol.Chem.277 (37): 34443-34450,2002).This structuring limits its chemical syntheses
With yield when biosynthesis, reason is to be difficult to fold into correct conformation.Although have recently patent for instruct in yeast
Middle synthesis overall length GsMTx-4 polypeptide, but cost and yield are still the bottleneck of drug development.
Summary of the invention
In view of in above-mentioned and/or existing biomedicine technical field to analgesic medicine develop there are the problem of, propose
The present invention.
Therefore, the one of purpose of the present invention is to provide one group of small peptide with analgesic activity.
In order to solve the above technical problems, according to an aspect of the present invention, the present invention provides the following technical scheme that one group
Peptide has any amino acid sequence as shown in (1)~(8): (1) the amino acid sequence as shown in sequence table SEQ ID No.1
Column；(2) amino acid sequence as shown in sequence table SEQ ID No.2；(3) amino acid as shown in sequence table SEQ ID No.3
Sequence；(4) amino acid sequence as shown in sequence table SEQ ID No.4；(5) amino as shown in sequence table SEQ ID No.5
Acid sequence；(6) amino acid sequence as shown in sequence table SEQ ID No.6；(7) ammonia as shown in sequence table SEQ ID No.7
Base acid sequence；(8) amino acid sequence as shown in sequence table SEQ ID No.8；Or, their pharmaceutically acceptable salt.
A kind of preferred embodiment as peptide of the present invention, in which: on the basis of existing for the head end and terminal cysteine,
In any peptide in (1) described in claim 1~(8), one or more amino acid are deleted, still have analgesia after displacement or addition
The polypeptide of effect is or, their pharmaceutically acceptable salt.
A kind of preferred embodiment as peptide of the present invention, in which: any shown in (1)~(8) that there is analgesia to make
Amino acid sequence or their pharmaceutically acceptable salt, wherein head end and two cysteines of end form ring.
A kind of preferred embodiment as peptide of the present invention, in which: it is obtained by chemical synthesis or by recombinant technique.
A kind of preferred embodiment as peptide of the present invention, in which: itself and protein fusion.
A kind of preferred embodiment as peptide of the present invention, in which: it is coupled with polymer.
A kind of preferred embodiment as peptide of the present invention, in which: the peptide is connect with carrier.
Another purpose of the invention is to provide a kind of pharmaceutical composition with analgesic activity.
In order to solve the above technical problems, according to another aspect of the present invention, the present invention provides the following technical scheme that
A kind of pharmaceutical composition, which is characterized in that including (1) a effective amount of described peptide as active constituent；(2) selective
Pharmaceutically acceptable carrier.
A kind of preferred embodiment as pharmaceutical composition of the present invention, in which: the pharmaceutically acceptable carrier choosing
From: solvent, diluent, suspending agent, emulsifier, antioxidant, pharmacy preservative, colorant, flavouring agent, medium, oiliness substrate,
One or more of excipient.
It is a still further object of the present invention to provide one group of peptide or they pharmaceutically acceptable salt or pharmaceutical composition exist
The application of ease pain.
The present invention passes through by comparing a variety of polypeptide sequences containing cysteine knot (ICK) such as GsMTx-4, GsMTX-2
Behaviouristics detection to rat pain model, has determined the pharmacophore (structural domain) that analgesic activity is played in GsMTx-4 polypeptide.This
The part of polypeptide segment of invention discovery GsMTx-4 plays the role of the inhibition of pain no less than overall length.Its principle is polypeptide GsMTx-4
Only have 11% identical (28% is similar) with GsMTx-2 amino acid sequence, but belongs to the special inhibition of mechanosensitive ion channels
Agent, although other several toxin amino acid sequences and GsMTx-4 homology it is higher (such as: the ammonia of GsMTx-4 and Hanatoxin
Base acid sequence has nearly 28% identical, and 37% is similar), but the blocking agent of other different type ion channels.It is of the invention in this way
Sequence of the people based on polypeptide GsMTx-4 key domain passes through a series of short chain polypeptides of commercialized chemical synthesis.By more
For peptide to the testing result of rat nociceptive pain model, inventor confirms to have obtained the short chain series of the polypeptide with analgesic activity,
Complete the present invention.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, required use in being described below to embodiment
Attached drawing be briefly described, it should be apparent that, drawings in the following description are only some embodiments of the invention, for this
For the those of ordinary skill of field, without any creative labor, it can also be obtained according to these attached drawings other
Attached drawing.Wherein:
Fig. 1 is to utilize vola locally injecting administration mode, SEQ ID No.1, GsMTx-4 and morphine in rats hyperalgia
Analgesic effect schematic diagram.To keep data reliability high, we use Normal Saline (Saline) as Negative controls, morphine
(Morphine) it is used as positive control.The present invention relates to all experiments and to take double-blind method.
Fig. 2 is SEQ ID No.1, GsMTx-4 and the hyperalgesic town of morphine in rats in the way of intraperitoneal injection
Pain effect schematic diagram.
Fig. 3 is that short chain polypeptides SEQ ID No.1 and overall length GsMTx-4 are eased pain by vola (A), abdominal cavity (B) injection system
Effect comparison and SEQ ID No.1 and GsMTx-4 analgesic activity dose dependent schematic diagram (C).
Fig. 4 is that SEQ ID No.2 eases pain to rat when passing through vola (A, B) or abdominal cavity (C, D) drug administration by injection mode respectively
Act on schematic diagram, and respectively with the contrast schematic diagram (B, D) of full-length polypeptide GsMTx-4 analgesic effect.
Fig. 5 is when SEQ ID No.3 passes through vola (A, B) or the administration of abdominal cavity (C, D) injection system respectively to the rat pain sensation
The schematic diagram of the analgesia benefit of allergy, and respectively with the contrast schematic diagram (B, D) of full-length polypeptide GsMTx-4 analgesic effect.
Fig. 6 is when SEQ ID No.4 passes through vola (A, B) or abdominal cavity (C, D) drug administration by injection respectively to rat hyperalgia
Analgesia benefit schematic diagram, and respectively with the contrast schematic diagram (B, D) of full-length polypeptide GsMTx-4 analgesic effect.
Fig. 7 is that SEQ ID No.5, SEQ ID No.6, SEQ ID No.7, SEQ ID No.8 pass through Rats With Unilateral respectively
Analgesic activity schematic diagram when hind leg vola locally injecting mode is administered.
Fig. 8 be SEQ ID No.6 (A, B) and SEQ ID No.8 (C, D) respectively by way of intraperitoneal injection when to rat pain
Feel allergy inhibiting effect schematic diagram.
Fig. 9 is that SEQ ID No.1, SEQ ID No.3 and full-length polypeptide GsMTx-4 (do not establish pain to normal rat
When pain model) pain threshold do not have an influential schematic diagram, and morphine is as right on the influential positive of normal rat pain threshold tool
According to.
Specific embodiment
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, right with reference to the accompanying drawings of the specification
A specific embodiment of the invention is described in detail.
In the following description, numerous specific details are set forth in order to facilitate a full understanding of the present invention, but the present invention can be with
Implemented using other way described herein is different from, those skilled in the art can be without prejudice to intension of the present invention the case where
Under do similar popularization, therefore the present invention is not limited by the specific embodiments disclosed below.
Secondly, " one embodiment " or " embodiment " referred to herein, which refers to, may be included at least one realization side of the invention
A particular feature, structure, or characteristic in formula." in one embodiment " that different places occur in the present specification not refers both to
The same embodiment, nor the individual or selective embodiment mutually exclusive with other embodiments.
According to all peptide sequences that general agreement writing book text refers to, wherein N-terminal amino acid is on the left side, and C-terminal amino
Acid is on the right.Short-term between two amino acid residues indicates peptide bond.
The compound of the present invention can be provided in the form of pharmaceutical salts.The example of preferred salt be with pharmaceutically acceptable organic acid and
Those of polymeric acid formation and the salt formed with inorganic acid, the organic acid such as acetic acid, lactic acid, maleic acid, citric acid, apple
Acid, ascorbic acid, succinic acid, benzoic acid, salicylic acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid or pamoic acid, the polymerization
Acid such as tannic acid or carboxymethyl cellulose, the inorganic acid such as halogen acids (for example, hydrochloric acid, sulfuric acid or phosphoric acid etc.).This can be used
The known any method for obtaining pharmaceutical salts of field technical staff.
In order to describe convenience of the invention, the conventional and unconventional abbreviation of various amino acid residues is used.These abbreviations are
Familiar to those skilled in the art, but in order to clearly be listed below:
Asp=D=aspartic acid；Ala=A=alanine；Arg=R=arginine；
Asn=N=asparagine；Gly=G=glycine；Glu=E=glutamic acid；
Gln=Q=glutamine；His=H=histidine；Ile=I=isoleucine；
Leu=L=leucine；Lys=K=lysine；Met=M=methionine；
Phe=F=phenylalanine；Pro=P=proline；Ser=S=serine；
Thr=T=threonine；Trp=W=tryptophan；Tyr=Y=tyrosine；
Val=V=valine；Cys=C=cysteine.
Overview
Present disclosure is characterized in for treating pain (such as all pain such as Acute Pain, chronic ache, cancer pain
Type) new type of peptides.Peptide can reduce pain sensitivity, therefore have analgesic activity.The peptide can produce long-acting analgesic and/or anti-wound
Evil sensitization.Medicine there is also described herein the concrete application method (such as treating pain) of this kind of peptide and containing this kind of peptide
Or composition.
Pain and nociception
International pain Research Society (International Association for the Study of Pain,
IASP) pain is defined as to " a kind of offending sensibility, emotionality are experienced, we mainly contact it with histologic lesion
Together, it is perhaps described in terms of histologic lesion or is not only associated with histologic lesion but also is described in terms of damage ".
Symptom or the pain itself that pain can be potential disease or illness are a kind of disease.Pain may be generally divided into two classes
Type: acute and chronic.Primary difference is that Acute Pain shields after damage, and chronic ache does not play this.
Acute Pain is pain symptom；And chronic ache is pain disease.
Most of Acute Pain is caused by disease, inflammation or tissue damage.The types of pain is generally in such as wound or outer
Occur suddenly after section's operation, and can be with anxiety or depressed.The reason of Acute Pain can be usually diagnosed to be and to it
It is treated, and pain is often self limiting, that is to say, that it is limited to special time period and serious.In some cases,
Acute Pain can be transformed into chronic ache.
Generally believe chronic ache inherently disease.Environment and psychological factor can be allowed to deteriorate.Chronic ache is than acute
Durante dolors are longer, and can be resistant to many drug therapies.
According to Clinical symptoms, the main Types of deducibility constant pain mechanism.Presumptive physiopathologic classification,
Pain syndrome is broadly divided into nociception, neuropathic, spirituality, mixed type or special hair style.
Analgesia peptide
Present disclosure, which provides, to be had analgesic properties and can be used for treating pain (such as Acute Pain, chronic ache or cancer
Pain etc.) peptide.The peptide can have Antinociceptive effect.
One of them of the invention is designed to provide one group of peptide (such as SEQ ID No.1~SEQ with analgesic activity
ID No.8).And the preparation method of this group of peptide be by synthesis, purifying, elution so that the sample purity of final synthetic peptide >
99%, and its molecular weight is measured using electrospray ionization mass spectrum (ESI-MS).
Certainly, those skilled in the art can recognize, on the basis of existing for the head end and terminal cysteine, SEQ ID
In any peptide of No.1~SEQ ID No.8, one or more amino acid are deleted, still have analgesic activity after displacement or addition
Polypeptide or, their pharmaceutically acceptable salt, still fall within protection scope of the present invention.
It is obtained peptide shown in SEQ ID No.1~SEQ ID No.8 by chemical synthesis or by recombinant technique, no
But it can be coupled, can also be connect with carrier with protein fusion or with polymer.Further study show that this group of peptide has
Special structure, any amino acid sequence or their medicines with analgesic activity shown in SEQ ID No.1~SEQ ID No.8
Acceptable salt on, wherein head end and two cysteines of end form ring.Such as following structures:
Embodiment
1. experimental animal, instrument and reagent
It grows up Sprague-Dawley male rat (8 weeks or more), weight 180g-220g, purchase is pleased in Jinan, Shandong Province friend
Experimental animal breeds Co., Ltd.
Carrageenan (Carrageenan is abbreviated as Carr) is U.S. sigma Products, prepares 1% Irish moss respectively
Glue (0.1g carrageenan is dissolved in 0.9% normal saline solution of 10ml, and packing to 10 EP is managed) and 2% carrageenan (0.2g
Carrageenan is dissolved in 0.9% normal saline solution of 10ml, and packing to 10 EP is managed), it is saved in -20 DEG C, uses preceding half an hour
It takes out and places on ice.
GsMTx-4 is bought from U.S. alomone labs, and all polypeptides of SEQ ID No.1~SEQ ID No.8 use height
Deionized water (DD water) after temperature sterilizing is configured to the mother liquor of 5mM or 10mM, and saves after being divided in EP pipe in -80 DEG C,
Concentration when use with normal saline dilution to needed for testing.
38500-PAM pressure application measuring system (Μ go Basile Biological Research Apparat μ s,
Comerio-Varese, Italy) consist of two parts, a part is handheld unit, and another part is integrated electronics unit.Hand
Holding unit is force snesor, which designed according to Randall-Selitto pain threshold detector, and integrated electronics unit can be certainly
Dynamic record is applied to the maximum mechanical paw withdrawal reflex threshold in rats with left metapedes vola.
2. the preparation of inflammatory pain model: we take two different inflammatory pain model preparation methods, are respectively used to vola
It is detected with the analgesic effect of abdominal cavity drug injection:
1% carrageenan inflammatory pain model of 2-1:6 μ l: according to document (Alessandri-Haber N, et
al.Neurosci.Vol 29(19),pp 6217-6288,2009)；The method of introduction prepares carrageenan inflammatory pain model.It should
Method is used for the detection of subplantar injection administration mode medicine analgesic effect.Briefly: from inserting needle between the left back foot 2 of rat, 3 toes,
1% carrageenan is injected, injection volume is 6 μ l, which, which can induce, generates hyperalgia, it may be assumed that after injection in half an hour
In The Rat Sole is the reduction for swelling and pain threshold occur.Mechanical paw withdrawal reflex threshold is in 50gf or less person as carrageenan inflammation
Property pain modeling success rat.Inflammatory threshold value is given in the inflammatory model rat of 50gf or more and is rejected.
2% carrageenan inflammatory pain model of 2-2:50 μ l: according to document (Seung Pyo Park, et
Al.2008.Pain.137:208-217) method introduced prepares 2% carrageenan inflammatory pain model.The method is for being injected intraperitoneally
The detection of administration mode medicine analgesic effect.Briefly: from inserting needle between the left back foot 2 of rat, 3 toes, injecting 2% carrageenan
50 μ l, which, which can induce, generates hyperalgia, it may be assumed that In The Rat Sole is more serious swell occur in half an hour after injection
Swollen and pain threshold reduction.Mechanical paw withdrawal reflex threshold reduces below qualified as the modeling of carrageenan inflammatory pain in 50gf
Rat.Inflammatory threshold value is given in the inflammatory model rat of 50gf or more and is rejected.
3. experimental group and animal processing
The 6 week old SD rats that all experimental rats are bought from Jinan, Shandong Province Peng Yue Company of Animals Ltd..Experimental rat adapts to
Property raising 2~4 weeks, feeding environment temperature is 22~26 DEG C, humidity 30%~50%, selects weight every time after adaptive feeding
The rat of 180~220g 10~12 measures rats with left metapedes machinery paw withdrawal threshold value, and every rat is taken to measure 5 mean values
As basic value (Baseline is abbreviated as BL) before the rat inflammatory modeling, reject basic value difference it is big or to mechanical stimulus without
The rat of reaction；Then it (is used according to the method for document introduction in 6 μ l of rats with left metapedes vola intracutaneous injection, 1% carrageenan
In subplantar injection dosing method) or 50 μ l, 2% carrageenan (for dosing method to be injected intraperitoneally), it is left that rat is detected after 1 hour
Side metapedes mechanicalness paw withdrawal threshold value, reject modeling failure (inflammatory threshold value 50gf or more) rat, by the successful rat of modeling
It is equally divided into medicine group and two groups of physiological saline group.It is all in the above operation to occur the feelings that modeling is unsuccessful, rat is removed
Condition, then plus test to ensure that every group of rat for statistical data is at least 5~8.
Effect --- the measurement of mechanical paw withdrawal reflex threshold of 4.GsMTx-4 and its small peptide in inflammatory induction hyperalgia
4.1 subplantar injection morphines, GsMTx-4 and small peptide inhibit the measurement of Inflammatory hyperalgesia
GsMTx- is evaluated with the left back sufficient mechanicalness paw withdrawal threshold value of 38500-PAM pressure application measuring system measurement rat
4 and its effect of the small peptide in rat mechanical hyperalgesia.It needs to carry out paw withdrawal to rat before all rat behavior tests
Training, until every rat all can start recording rat basis paw withdrawal threshold value after paw withdrawal.The same day is needed to 10~12 rats surveyed
It is put into same mouse cage, is numbered on the tail of each rat from 1~10 (or 12), then allow rat suitable in measurement room
30min is answered, starts to test after rat is quiet.It is mounted on according to the force snesor that Randall-Selitto pain threshold detector designs
In one hand-held device unit of 38500-PAM pressure application measuring system.It is 0.45gf that the smallest force value, which is arranged, in measuring system,
Maximum force value is 450gf.Successively Digital size is successively by number with 38500-PAM pressure application measuring system by operator
Measure every rats with left metapedes machinery paw withdrawal threshold value.Specific method is that the cone point in handheld unit is first placed on a rat left side
Position among the metapedes vola of side then applies a power to rats with left metapedes with constant power rate (30gf/s), exerted forces
Maximum time is 15s, and in the 15s time when tested rat hindleg retraction, operator stops force, and electronic unit will be automatic at this time
Record is applied to the maximum mechanicalness paw withdrawal threshold value in rats with left metapedes vola, if left side metapedes does not go out yet after tested rat 15s
Existing paw withdrawal reflection, system meeting automatic alarm, operator stop measurement, duplicate measurements after 10min.If the multiple 15s of certain rat
Left side metapedes does not occur paw withdrawal reflection afterwards, rejects this rat.It successively successively measures, repeats according to rat tail numerical digit size
Measurement 5 times (each stimulus intervals time is 10min), the average value of 5 experiments is taken,.Intracutaneous injection 6 μ l in vola after measurement
1% carrageenan establishes rat inflammatory pain model.Detection rats with left metapedes mechanicalness contracting after injection carrageenan 1 hour
Sufficient threshold value rejects the rat (modeling failure) of threshold size exception.Higher mix with the lower rat of threshold value of inflammatory threshold value is put down
It is divided into 2 groups: medicine group and physiological saline group, every group 5~6, so that two groups of rat inflammatory threshold values distributions are similar.Medicine group exists
1.2 μ g/5 μ l GsMTx-4 (with suitable concentration is before diluted to) of rats with left metapedes vola intracutaneous injection or in which a kind of small peptide,
Or the subcutaneous same position of 5mg/kg morphine or rats with left metapedes vola injects the isometric physiological saline of 5 μ l, after injection respectively
Each group rats with left metapedes machinery paw withdrawal reflex threshold, the equal retest of every rat 5 times are detected in 1h, 3h, 5h, 7h and for 24 hours
(each test interval is 10min), taking the average value of 5 paw withdrawal reflex thresholds is the practical paw withdrawal reflex threshold of the rat
(unit are as follows: g).
Note: it is all in the above operation the case where modeling is unsuccessful, rat is removed occur, then plus test to ensure every group
Rat for Exemplary statistical data is at least 5~8.
4.2 intraperitoneal injection GsMTx-4 and its small peptide inhibit the measurement of Inflammatory hyperalgesia
GsMTx-4 is injected intraperitoneally and its small peptide inhibits the method and step of Inflammatory hyperalgesia similar to subplantar injection, but has
It is some different:
(1) it is 0.75gf that the smallest force value, which is arranged, in the measuring system, and maximum force value is 750gf
(2) in view of intraperitoneal injection morphine may cause mechanicalness paw withdrawal threshold value substantial increase, most by exerted forces
The big time is adjusted to 25s
(3) 270 μ g/kg GsMTx-4 or in which a kind of small peptide or 10mg/kg morphine, physiological saline is injected intraperitoneally in medicine group
Group intraperitoneal injection amount be etc. quality sterile saline.
Based on above-mentioned experiment, Fig. 1 GsMTx-4, morphine and SEQ ID No.1 pass through vola subcutaneous administrations mode
(volume injected is 6 μ l) is to the schematic diagram of rat hyperalgia inhibitory effect.Wherein, A figure show left back in rat in advance
After 6 μ l of whole bottom intracutaneous injection, 1% carrageenan (Carr) induced rat inflammatory model, 5 are injected at In The Rat Sole swelling position
After the physiological saline 1h, 3h, 5h of μ l, rat machinery paw withdrawal threshold value and inflammatory threshold value no significant difference；And it contracts with mechanical before modeling
Foot reflex threshold value is compared, and morphine (B), GsMTx-4 (C) or the SEQ ID No.1 (D) of equal volume amounts (5 μ l) are significantly reduced
Rat machinery paw withdrawal reflex threshold.For example isometric GsMTx-4 or small peptide SEQ ID is subcutaneously injected in In The Rat Sole swelling position
After No.1 (injection volume is 1.2 μ g/5 μ l) 1h, 3h, 5h, rat machinery paw withdrawal threshold value, which has, to be increased, and 3h reaches most after injection
It is high.Notice that morphine drug effect after 1h is administered reaches maximum value, but increasing for rat machinery paw withdrawal threshold value greatly exceeds rat baseline
Mechanical paw withdrawal threshold value when (Base Line, be abbreviated as BL).It is considered that be more than baseline may with morphine it is additive,
Rely related to its toxicity by property.E figure is with big in left back whole 6 μ l of bottom intracutaneous injection, 1% carrageenan (Carr) induction of rat
Compare GsMTx-4, small peptide SEQ ID No.1 and physiological saline and morphine in rats mechanical hyperalgesia after mouse inflammatory model
In inhibiting effect.
Fig. 2 is GsMTx-4, morphine and SEQ ID No.1 right by intraperitoneal injection mode (volume injected is 50 μ l)
The contrast schematic diagram of rat hyperalgia inhibiting effect.We have obtained and prior figures 1 (subplantar injection) is similar to pain sensation mistake
Quick inhibiting effect, but there is GsMTx-4 and SEQ ID No.1 stronger inhibition when the mode than being administered from vola intracutaneous injection to make
With: they reach maximum suppression effect after 3h, and can be totally turned over by carrageenan (Carr: injection volume be 50 μ l
2%) the inflammatory pain threshold value (B, C) induced, and physiological saline does not act on (A).In addition, morphine (injection volume 10mg/Kg)
Highest is reached to rat hyperalgia inhibiting effect after injecting 1h, although than GsMTx-4 (injection volume is 270 μ g/Kg, 50 μ l)
It is higher by one times (see E) with the analgesic activity of SEQ ID No.1 (injection volume is 270 μ g/Kg), but with subplantar injection administration mode
As a result similar: although morphine analgesic activity is stronger, rat having been greatly exceeded to the raising of rat machinery paw withdrawal threshold value
Baseline threshold (Base Line, be abbreviated as BL), it is believed that this part is related to the toxicity of morphine.In addition, after 3h morphine town
Pain acts on decline rapidly, achievees the effect that there is similar analgesic activity (E) to GsMTx-4 and SEQ ID No.1.Due to the present invention
Even if the short chain polypeptides with most strong analgesic activity proposed are no on the normal rat pain sensation to influence (see Fig. 9), therefore this hair
The polypeptide of bright discovery is possible to develop into the hyperalgesic best analgesic for the treatment of or intermixture.
Fig. 3 is the contrast schematic diagram of SEQ ID No.1 Yu overall length GsMTx-4 analgesic activity.SEQ ID No.1 and GsMTx-
4 by subplantar injection mode when being administered, and analgesic activity does not have notable difference (A, C in figure), and wherein C is SEQ ID No.1 (right side)
Pass through the dose-dependant figure of analgesic activity when subplantar injection mode with overall length GsMTx-4 (left side).But when the two passes through abdominal cavity respectively
When injection system is administered, SEQ ID No.1 may have stronger analgesic effect (B in figure).
Fig. 4 is the analgesic activity schematic diagram that SEQ ID No.2 passes through vola (A), abdominal cavity (C) administration mode respectively.In order to
The analgesic effect of the analgesic effect of more preferable relatively short chain polypeptides, equivalent overall length GsMTx-4 compares (B, D) by light gray expression.
Wherein A is illustrated after left back whole 6 μ l of bottom intracutaneous injection, 1% carrageenan (Carr) of rat, anti-with paw withdrawal mechanical before modeling
It penetrates threshold value to compare, hence it is evident that reduce rat machinery paw withdrawal reflex threshold, SEQ ID No.2 is subcutaneously injected in vola, and (injection volume is 1.2 μ
G/5 μ l) 1h, 3h, 5h, after 7h, rat machinery paw withdrawal threshold value increases, and 1-3h reaches highest after injection.C diagram is intended to rat
(injection volume is 270 μ by left back 2% carrageenan (Carr) of whole 50 μ l of bottom intracutaneous injection 1h afterwards, intraperitoneal injection SEQ ID No.2
G/Kg there is rat machinery paw withdrawal threshold value after) 1h, 3h, 5h, 7h increases, and inhibiting effect is most strong when injection 3h, it is evident that abdominal cavity note
The analgesic activity for penetrating administration is better than vola topical modes.Furthermore intraperitoneal injection SEQ ID No.2 has and overall length GsMTx-4
Similar analgesic activity (D).
Fig. 5 is that SEQ ID No.3 passes through vola (A) respectively, abdominal cavity (C) administration mode shows hyperalgesic inhibiting effect
It is intended to.Wherein, shown in A figure after left back whole 6 μ l of bottom intracutaneous injection, 1% carrageenan (Carr) of rat, with machinery before modeling
Paw withdrawal reflex threshold is compared, obvious after vola subcutaneous injection SEQ ID No.3 (injection volume is 1.2 μ g/5 μ l) 1h, 3h, 5h, 7h
Rat machinery paw withdrawal reflex threshold is reduced, and 3h reaches highest after injection.B scheme shown in SEQ ID No.3 with it is subcutaneous in vola
Rat machinery paw withdrawal reflects threshold after quality, isometric GsMTx-4 (1.2 μ g/5 μ l) or the physiological saline 1h, 3h, 5h, 7h such as injection
The comparison of value, SEQ ID No.3 do not have notable difference (B) to hyperalgesic inhibiting effect and full-length polypeptide GsMTx-4 small peptide,
Saline rats machinery paw withdrawal threshold value simultaneously has not been changed.C figure is shown in left back whole 2% jiao of 50 μ l of bottom intracutaneous injection of rat
After pitching dish glue (Carr), by intraperitoneal injection SEQ ID No.2 (injection volume be 270 μ g/Kg) 1h, 3h, 5h, after 7h and before modeling
Mechanical paw withdrawal reflex threshold is compared, and rat machinery paw withdrawal threshold value obviously increases, and 3h is totally turned over the machine of rat after injection
Tool paw withdrawal threshold value does not have notable difference with rat baseline (baseline:BL before modeling).Therefore it is given by intraperitoneal injection mode
SEQ ID No.3 may have analgesic effect (D) more stronger than equal quality full-lengths polypeptide GsMTx-4 when medicine.
Fig. 6 is that SEQ ID No.4 passes through vola (A) respectively, abdominal cavity (C) administration mode shows hyperalgesic inhibiting effect
It is intended to.Wherein, shown in A figure after left back whole 6 μ l of bottom intracutaneous injection, 1% carrageenan (Carr) of rat, with machinery before modeling
Paw withdrawal reflex threshold is compared, obvious after vola subcutaneous injection SEQ ID No.4 (injection volume is 1.2 μ g/5 μ l) 1h, 3h, 5h, 7h
Rat machinery paw withdrawal reflex threshold is reduced, and 3h reaches highest after injection.B figure show SEQ ID No.4 and in vola skin
Rat after the physiological saline 1h, 3h, 5h, 7h of the quality such as lower injection/isometric GsMTx-4 (1.2 μ g/5 μ l) or isometric (5 μ l)
The comparison of mechanical paw withdrawal reflex threshold, SEQ ID No.4 to hyperalgesic inhibiting effect slightly than full-length polypeptide GsMTx-4 small peptide
It is weak.After C is shown in the inflammation inducing swelling of the left back whole 50 μ l of bottom intracutaneous injection 2% carrageenan (Carr) of rat, pass through abdominal cavity
Injecting SEQ ID No.4, (injection volume is 270 μ g/Kg) compared with paw withdrawal reflex threshold mechanical before modeling, 1h, 3h, big after 5h, 7h
Mouse machinery paw withdrawal threshold value obviously increases, and rat machinery paw withdrawal threshold value and rat baseline (BL) are no obvious after 3h after injection
Difference.When being therefore administered by intraperitoneal injection mode, the analgesic activity of SEQ ID No.4 and equal quality full-lengths polypeptide GsMTx-4
Analgesic activity there is no notable difference (D).
Fig. 7 shows tri- kinds of SEQ ID No.5, SEQ ID No.6, SEQ ID No.7 small peptides and passes through intraperitoneal injection mode
To the hyperalgesic inhibiting effect of rat when administration.Wherein, A illustrates vola subcutaneous injection SEQ ID No.5 (1.2 μ g/5 μ l)
After 1h, 3h, 5h, 7h, compared with Carr inflammatory model rat machinery paw withdrawal threshold value, mechanical paw withdrawal threshold value is all significantly improved,
And reach highest in 3h.After B shows vola subcutaneous injection SEQ ID No.6 (1.2 μ g/5 μ l) 1h, 3h, with Carr inflammatory
Threshold value is compared, and mechanical paw withdrawal threshold value is all significantly improved, and reaches highest in 3h.And C illustrates vola subcutaneous injection SEQ ID
After No.7 (1.2 μ g/5 μ l) 1h, 3h, 5h, 7h, compared with Carr inflammatory threshold value, mechanical paw withdrawal threshold value is all significantly improved, and
Reach highest in 3h.After D illustrates vola subcutaneous injection SEQ ID No.8 (1.2 μ g/5 μ l) 1h, 3h, 5h, 7h, with Carr inflammation
Property threshold value is compared, and mechanical paw withdrawal threshold value is all significantly improved, and reaches highest in 3h.
Fig. 8 is shown when SEQ ID No.5 and SEQ ID No.8 is administered by intraperitoneal injection mode to rat inflammatory pain
Analgesic activity.Wherein A and C figure is illustrated respectively in left back whole 50 μ l of bottom intracutaneous injection, 2% carrageenan (Carr) of rat and lures
After leading inflammatory pain, then by intraperitoneal injection SEQ ID No.5 (A figure) or SEQ ID No.8 (C figure), (injection volume is respectively
270μg/Kg).Compared with rat inflammatory model machinery paw withdrawal reflex threshold (Carr), 1h, 3h, rat machinery paw withdrawal after 5h, 7h
Threshold value obviously increases, and 3h reaches maximum value after injection.Therefore, SEQ ID No.5 (B figure) and SEQ ID is injected intraperitoneally
No.8 (D figure) has similar analgesic activity to overall length GsMTx-4, and wherein SEQ ID No.8 effect is slightly stronger, holds time more
It is long.There is no notable difference (D figure) with the analgesic activity of full-length polypeptide after 5h.
Fig. 9 diagram GsMTx-4, SEQ ID No.1 and SEQ ID No.3 do not have shadow to the mechanical paw withdrawal threshold value of normal rat
It rings.A is shown in the left back whole subcutaneous direct injection morphine in bottom of normal rat, and (injection volume 5mg/kg, the dosage are usually morphine
The minimum dose of dosage) after 1h, one times of mechanical paw withdrawal reflex threshold or more (threshold of the further strong inhibition normal rat of morphine
Value rises to 550g from average~250g of normal rat), it is believed that while this plays analgesic activity with morphine, have
It is additive related to toxicity.B, C, D figure be shown in respectively the left back whole subcutaneous direct injection GsMTx-4 in bottom (A figure) of normal rat,
(injection volume is 1.2 μ g/5 μ l, which is GsMTx-4 and SEQ by SEQ ID No.1 (B figure) or SEQ ID No.3 (C figure)
Inhibit rat hyperalgesic maximum dose when ID No.1 is administered by subplantar injection mode) 1h, 3h, 5h, after 7h, equal not shadows
Ring the mechanical paw withdrawal reflex threshold of normal rat.Since GsMTx-4, SEQ ID No.1 and SEQ ID No.3 are involved by the present invention
And with the short chain of polypeptide of most strong analgesic activity in peptide, therefore group experiment demonstrates again that polypeptide pair of the present invention from the negative
Normal rat is without secondary (toxicity) effect.
Pharmaceutical composition
The peptide of present disclosure can be configured to for example give pharmaceutical composition of the subject to treat pain.Peptide can be with
It individually gives, or can be given in combination in same composition or as individual composition with other Pain treatments.
Pharmaceutical composition generally includes pharmaceutically acceptable carrier." pharmaceutically acceptable carrier " used herein packet
Include solvent, decentralized medium, coating material, antibacterial agent and antifungal agent, isotonic agent and the suction of any and all physical compatibility
Receive delayer etc..Composition may include pharmaceutically acceptable salt, such as acid-addition salts or base addition salts.
Drug preparation technique is generally accepted technology, and more details is see, for example, Gennaro, The Science and
Practice of Pharmacy, the 20th edition, Lippincott, Williams&Wilkins (2000) (ISBN:
0683306472)；Ansel etc., Pharmaceutical Dosage Forms and Drug Delivery Systems, the 7th
Version, Lippincott Williams&Wilkins Publishers (1999) (ISBN:0683305727)；And Kibbe,
Handbook of Pharmaceutical Excipients American Pharmaceutical Association, the 3rd
Version (2000) (ISBN:091733096X).
In one embodiment, (such as salt water, sodium chloride, disodium hydrogen phosphate seven are hydrated for the peptide and excipient materials
Object, sodium dihydrogen phosphate) and stabilizer prepare together.It can also be provided in such as buffer solution by suitable concentration.
Pharmaceutical composition can take various forms.These include such as liquid, semisolid and solid dosage forms, such as liquid solution
Agent (such as injection and infusion solution), dispersing agent or suspension, tablet, pill, powder, liposome and suppository.Preferred shape
Formula may depend on set administration mode and treatment use.
Composition can be given by parenteral (such as in intravenous, subcutaneous, peritonaeum or intramuscular injection).It is used herein
Term " parenteral " and " parenterally giving " refer to the administration mode other than enteral and local administration, usually through being administered to
Medicine, include but not limited to intravenous, intramuscular, intra-arterial, in intrathecal, intracapsular, socket of the eye, in heart, in intradermal, peritonaeum, transtracheal,
Subcutaneously, under epidermis, under intra-articular, capsule, under arachnoid, intraspinal, Epidural cavity and breastbone inner injection and infusion.
Composition can be given through enteral route, such as passes through alimentary canal, such as oral administration.For example, can be with tablet, glue
Wafer, caplet agent, pill, powder, drops, suspension, solution, paste, gelling agent or other peroral dosage forms give composition.
Enteral route includes through stomach feeding tube, duodenum feeding tube or gastrostomy or rectal administration, such as with suppository or bowel lavage
The composition of dosage form formula.
Composition can local administration, such as in painful area.Local administration includes such as epidermis, intranasal, sucking and vagina
Administration.Composition can be given to skin (such as burn, blister or cut), lip, gum, tooth, oral cavity, eye, ear, nail matrix or throat
Deng, such as painful area.The composition of local administration can be cream, gelling agent, lotion or ointment etc..
Pharmaceutical composition may include the peptide as described herein of " therapeutically effective amount ".The effective quantity can be according to given drug (example
Such as peptide) effect determine, or if when using more than one drugs, determined according to combination effect.The medicine of therapeutically effective amount
Object can also change according to following factor: types of pain, disease condition, age, gender and the weight of such as subject and
Drug causes the ability of required reaction (such as improving pain) in subject's body.Therapeutically effective amount is also wherein composition
Beneficial effect is treated more than any toxicity or the amount of illeffects.
Based on the present invention, be possible to obtain in the future it is a kind of it is novel, for analgesic polypeptide drugs, or contain the polypeptide
Effectively analgesia mixture.Present invention has the advantage that
1. primary spider toxin GsMTx-4 polypeptide forms four cyclic structures in water, when synthesis, requires polypeptide that must roll over
It builds up and keeps the space structure of the native polypeptide that just there is corresponding drug effect, therefore synthesis procedure is cumbersome at high cost.The present invention is found
The pharmacophore of analgesic activity is played in native polypeptide, therefore reduces the synthesis cost of polypeptide, makes industrially to produce in enormous quantities
Become efficient and cheap；
2. reducing immunogenicity since the present invention reduces polypeptide length, it is easier to absorption of human body.In clinical application
Drug effect can more be given full play to.Due to the polypeptide on the pain threshold normally belonged to greatly do not influence to compare with drugs such as morphines without at
Addiction, without drug dependence and nontoxicity.Therefore the present invention may be developed as clinically widely applied analgesic.
It should be noted that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to preferable
Embodiment describes the invention in detail, those skilled in the art should understand that, it can be to technology of the invention
Scheme is modified or replaced equivalently, and without departing from the spirit and scope of the technical solution of the present invention, should all be covered in this hair
In bright scope of the claims.
SEQUENCE LISTING
<110>Xuzhou medical university
<120>one groups of peptide and its pharmaceutical composition and applications
<130> 2016
<160> 9
<170> PatentIn version 3.3
<210> 1
<211> 17
<212> PRT
<213>artificial sequence
<400> 1
Trp Lys Cys Asn Pro Asn Asp Asp Lys Cys Cys Arg Pro Lys Leu Lys
1 5 10 15
Cys
<210> 2
<211> 11
<212> PRT
<213>artificial sequence
<400> 2
Trp Trp Lys Cys Asn Pro Asn Asp Asp Lys Cys
1 5 10
<210> 3
<211> 12
<212> PRT
<213>artificial sequence
<400> 3
Trp Lys Cys Ala Pro Ala Asp Asp Lys Cys Arg
1 5 10
<210> 4
<211> 11
<212> PRT
<213>artificial sequence
<400> 4
Trp Lys Cys Ala Pro Ala Asp Asp Lys Cys Ala
1 5 10
<210> 5
<211> 9
<212> PRT
<213>artificial sequence
<400> 5
Trp Cys Asn Pro Asn Asp Asp Lys Cys
1 5
<210> 6
<211> 9
<212> PRT
<213>artificial sequence
<400> 6
Trp Cys Lys Pro Asn Asp Asp Lys Cys
1 5
<210> 7
<211> 9
<212> PRT
<213>artificial sequence
<400> 7
Trp Cys Asn Asp Asp Lys Cys
1 5
<210> 8
<211> 9
<212> PRT
<213>artificial sequence
<400> 8
Trp Cys Lys Asp Asp Lys Cys
1 5
Claims (8)
1. a kind of peptide of analgesic activity, it is characterised in that: be any amino acid sequence as shown in (1)~(8):
(1) amino acid sequence as shown in sequence table SEQ ID No.1；
(2) amino acid sequence as shown in sequence table SEQ ID No.2；
(3) amino acid sequence as shown in sequence table SEQ ID No.3；
(4) amino acid sequence as shown in sequence table SEQ ID No.4；
(5) amino acid sequence as shown in sequence table SEQ ID No.5；
(6) amino acid sequence as shown in sequence table SEQ ID No.6；
(7) amino acid sequence as shown in sequence table SEQ ID No.7；
(8) amino acid sequence as shown in sequence table SEQ ID No.8；Or,
Their pharmaceutically acceptable salt；
Wherein, head end and two cysteines of end form ring.
2. peptide according to claim 1, it is characterised in that: it is obtained by chemical synthesis or by recombinant technique.
3. peptide according to claim 1 or 2, it is characterised in that: itself and protein fusion.
4. peptide according to claim 1 or 2, it is characterised in that: it is coupled with polymer.
5. peptide according to claim 1 or 2, it is characterised in that: the peptide is connect with carrier.
6. a kind of pharmaceutical composition, which is characterized in that including,
(1) a effective amount of peptide as described in Claims 1 to 5 is any as active constituent；
(2) selective pharmaceutically acceptable carrier.
7. pharmaceutical composition according to claim 6, which is characterized in that the pharmaceutically acceptable carrier is selected from: molten
Agent, diluent, suspending agent, emulsifier, antioxidant, pharmacy preservative, colorant, flavouring agent, medium, oiliness substrate, figuration
One or more of agent.
8. one group of peptide as described in claim 1 or their pharmaceutically acceptable salt or as described in claim 6 or 7
Application of the pharmaceutical composition in preparation treatment analgesic.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611128087.6A CN106632603B (en) | 2016-12-09 | 2016-12-09 | One group of peptide and its pharmaceutical composition and application |
| PCT/CN2017/118520 WO2018103761A1 (en) | 2016-12-09 | 2017-12-26 | Peptides, and pharmaceutical compositions and uses thereof |
Applications Claiming Priority (1)
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| CN201611128087.6A CN106632603B (en) | 2016-12-09 | 2016-12-09 | One group of peptide and its pharmaceutical composition and application |
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| CN106632603B (en) * | 2016-12-09 | 2019-05-17 | 唐琼瑶 | One group of peptide and its pharmaceutical composition and application |
| CN112940080A (en) * | 2021-03-30 | 2021-06-11 | 西南医科大学附属医院 | Polypeptide P10581 and application thereof in preparing medicine for relieving bone cancer pain |
| US11612634B2 (en) * | 2020-12-11 | 2023-03-28 | Xuzhou Medical University | Pharmaceutical composition and method for relieving/eliminating morphine-induced analgesic tolerance |
| CN112516284B (en) * | 2020-12-11 | 2021-12-21 | 徐州医科大学 | Application of short peptide in preparation of product with morphine tolerance elimination effect |
| CN112851785A (en) * | 2021-03-26 | 2021-05-28 | 徐州医科大学 | Short peptide with analgesic tolerance for relieving morphine in neuropathic pain and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004085647A1 (en) * | 2003-03-26 | 2004-10-07 | Pharmadesign, Inc. | Low-molecular weight peptides inhibiting ion channel activity |
| WO2007046634A1 (en) * | 2005-10-18 | 2007-04-26 | Seoul National University Industry Foundation | Method for preparing recombinant peptide from spider venom and analgesic composition containing the peptide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US7125847B1 (en) * | 2000-04-07 | 2006-10-24 | The Research Foundation Of State University Of New York At Buffalo | Mechanically activated channel blocker |
| WO2006014493A2 (en) * | 2004-07-07 | 2006-02-09 | The Research Foundation Of State University Of New York Stor | Mechanically activated channel blocker |
| US9211313B2 (en) * | 2011-01-14 | 2015-12-15 | The Research Foundation Of State University Of New York | Methods and compound to inhibit Ca2+ permeable cation conductance |
| JP2014084283A (en) * | 2012-10-19 | 2014-05-12 | Univ Of Yamanashi | Therapeutic agent for urination disorder |
| CN106632603B (en) * | 2016-12-09 | 2019-05-17 | 唐琼瑶 | One group of peptide and its pharmaceutical composition and application |
-
2016
- 2016-12-09 CN CN201611128087.6A patent/CN106632603B/en active Active
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2017
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004085647A1 (en) * | 2003-03-26 | 2004-10-07 | Pharmadesign, Inc. | Low-molecular weight peptides inhibiting ion channel activity |
| WO2007046634A1 (en) * | 2005-10-18 | 2007-04-26 | Seoul National University Industry Foundation | Method for preparing recombinant peptide from spider venom and analgesic composition containing the peptide |
Non-Patent Citations (2)
| Title |
|---|
| A synthetic peptide that may act as an inhibitor selective to mechanosensitive ion channels;QiongYao Tang et al.;《Proceedings of Annual Meeting of the Physiological Society of Japan 2005》;20051231;摘要 |
| Solution Structure of Peptide Toxins That Block Mechanosensitive Ion Channels;Robert E. Oswald et al.;《THE JOURNAL OF BIOLOGICAL CHEMISTRY》;20020913;34443-34450 |
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| WO2018103761A1 (en) | 2018-06-14 |
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