CN104497065B - α galactosyl ceramide Novel isomerics and application thereof - Google Patents
α galactosyl ceramide Novel isomerics and application thereof Download PDFInfo
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Abstract
The invention provides a kind of α galactosyl ceramides Novel isomeric and application thereof, the α galactosyl ceramides Novel isomeric changes into 4 in the configuration of sphingol chain, 5 cis-double bonds sphingol chains, it, which can be recognized by NKT cells and play stimulation, produces cell factor, the application potential for having immunotherapy of tumors.
Description
Technical field
The invention belongs to cell biology, specifically a kind of alpha-galactosylceramide Novel isomeric and application thereof.
Background technology
Find that the extract of Agelas mauritianus sponges contains in the Kirin Breweries etc. the nineties in 20th century
Bioactive molecule, rear synthesis compound a structure is shown in that Fig. 1 (a-galactosylceramide, a-GalCer, KRN7000) has and exempted from
Epidemic disease bioactivity.Alpha-galactosylceramide(KRN 7000)Be in glycosyl ceramide (glycosyl sphingolipid) family it is foremost into
Member, it is offered molecule CD1d by antigen and recognizes to form binary complex, then with NKT cell receptors(TCR)Interaction, activation
The signal transmission molecule for being responsible for intercellular communication is cell factor, cell factor Th1/Th2 immune responses activation it is specific other
Immunocyte(B cell, T cell, macrophage etc.)To play antitumor, antibacterial functions(Th1)Or protection body fight itself is exempted from
Epidemic disease(Th2).KRN7000 clinical research is not very successful, is primarily due to KRN7000 and produces the Th1 confronted with each other simultaneously
With Th2 type immune responses, the shortcoming of also one is overstimulation;It is necessary to develop new KRN7000 analogs energy selectivity,
Suitably activation NKT cells only produce Th1 types or Th2 type immune responses.
Due to wide application prospect yearning KRN 7000 and the defect of presence, the class for attracting last decade numerous
Advantage induction NKT cell Th1 cytokines secretion or advantage induction NKT cell Th2 cytokines point are looked in topic group research
The new alpha-galactosylceramide homologue secreted.
Through consulting, to sphingol chain(Sphingosine chain, are shown in Fig. 1 compound as)Configuration change after molecular activity
The rare report of research, conventional research is all the synthesis on 4,5 trans double bond sphingol chain derivatives(See Fig. 1, compound
c, e)With activity research, the alpha-galactosylceramide Novel isomeric that we invent is that have 4,5 cis-double bonds in sphingol chain
(See Fig. 2).It was noted that nearest relevant progress, although phospholipid antigen, the antigen of bacterial origin and α-galactolipin god
Lipid through acid amides homologue is different, structure is had any different, but cis-double bonds shows very obvious in antigen fat chain;Such as in phosphatide
Antigen research shows that NKT cells can recognize one or more double bond structures on one or two aliphatic chains, but this
Kind of double bond structure must be cis-configuration, only at least containing unrighted acid chain could by NKT cell recognitions,
And comprise only single double bond structure containing multiple double bond structure ratios and be easier to be identified, in addition, the unsaturation of increase acyl chain
Degree, the stability combined with the d molecules of CD 1 is consequently increased.To the discovery of antigen research of bacterial origin, its aliphatic acid is with suitable
Formula double bond oleic acid has immunocompetence.Found in the research of computer simulation, insert cis-double bonds on acid amides chain, make chain stiff, relatively
Relatively d molecules of CD 1.And the solubility of antigen can be improved with cis-double bonds, this experiment to bioactivity is critically important.
But the immunocompetence research of the 4,5 cis-double bonds sphingol chain derivatives to the alpha-galactosylceramide of synthesis(See Fig. 2, change
Compound 1a, 1b, 1c)Have not been reported.
The content of the invention
In order to solve the above-mentioned technical problem, the invention provides a kind of alpha-galactosylceramide Novel isomeric and its use
On the way.
A kind of alpha-galactosylceramide Novel isomeric, it is characterised in that it changes into 4 in the configuration of sphingol chain, 5 is suitable
Formula double bond sphingol chain.
Described a kind of alpha-galactosylceramide Novel isomeric, it is characterised in that with one or more suitable on its acyl chain
Formula double bond.
The purposes of described a kind of alpha-galactosylceramide Novel isomeric, it is characterised in that it can be by NKT cells institute
Recognize and play stimulation and produce cell factor.
Described purposes, it is characterised in that it preferentially induces Th1 cell factors.
Described purposes, it is characterised in that its purposes in immunotherapy of tumors.
Alpha-glycosylceramides Novel isomeric structure of the present invention is shown in Fig. 2.It is suitable that emphasis changes into 4,5 in the configuration of sphingol chain
Formula double bond sphingol chain, changing acid amides chain has different saturation, the new immune work of alpha-glycosylceramides Novel isomeric performance
Property preference.Immunocompetence experiment utilizes mouse source NKT- hybridomas and mouse source spleen lymphocyte vitro detection, wherein chemical combination
Thing 1b, 1c are suitable with tester KRN7000 immunocompetences in hybridoma experiment, show that it has immunocompetence, further
Immunization experiment is done, alpha-glycosylceramides Novel isomeric can show induction deviation, i.e., show in the experiment of mouse source spleen lymphocyte
Show preferential induction Th1 cell factors;The mouse source experiment in vivo of 3rd step, alpha-glycosylceramides Novel isomeric is still shown preferentially
Induce Th1 cell factors;In terms of the cell factor preference of its induction, alpha-galactosylceramide Novel isomeric 1b, 1c tool tumour
The application potential of immunization therapy.
Concrete scheme of the present invention is as follows:
It is used as NKT derivants, alpha-galactosylceramide Novel isomeric(1a-1c)Initial Bioactivity is determined
In, 1a, 1b, 1c can induce mouse source NKT cell hybrid knurls 2H4 and 2Cl2 generation proleulzin (IL-2).1a, 1b, 1c exist
It is suitable with KRN7000 activity in mouse source NKT cell hybrid knurls 2H4 experiment;To mouse source NKT cell hybrid knurls 2Cl2
Experiment in 1a, 1b, 1c is substantially higher than KRN7000 activity;Two experiments all show that acid amides chain belt double bond is conducive to activity to carry
It is high.(See Fig. 3,4)
In being tested to mouse source spleen lymphocyte stimulated in vitro, alpha-glycosylceramides Novel isomeric can be investigated(1b,
1c)Induction preference.What the splenocyte that compound 1b and 1c is capable of Fiber differentiation under 2.5 μ g/mL and 5 μ g/mL concentration was produced
IFN-g.What is interesting is, it has been found that 1c is that a-GalCer is pierced under 100ng/mL concentration in 5 μ g/mL concentration induction IFN-g
Sharp doubling dose(Such as Fig. 5).On the contrary, after being stimulated by compound 1b and 1c, the IL-4 secretory volumes of Th2 types are suitable low.Number
According to showing that compound 1b and 1c can recognize and acted as a spur that bioactivity is substantially embodied in excellent by NKT cells well
First induce Th1 cell factors.Alpha-galactosylceramide Novel isomeric 1b, 1c are new NKT stimulants, and compound 1b and
Inductions of the 1c to NKT cells has obvious selectivity;From mouse NKT hybridomas(Fig. 3,4), the primary splenocyte test in mouse source
(Fig. 5)With the internal test of mouse(Fig. 6), the activity of alpha-galactosylceramide Novel isomeric is consistent, i.e., immunocompetence is suitable
Sequence 1c > 1b > 1a, it is seen that two cis-double bonds ratio bands of band, one cis-double bonds is beneficial to improve immune biological living on amine acyl chain
Property, one cis-double bonds of band is higher than the acid amides chain activity of saturation;There is cis-double bonds number on the acyl chain of literature research ceramide
Mesh and the relation of activity, being further added by cis-double bonds number could not make activity increase obvious.
It can be seen from figure 1 that when 20 carbon long-chain of the acid amides chain all containing cis-double bonds, sphingol chain is phytosphingosine (chemical combination
Thing d), or 4, the sphingol of 5 trans double bonds(Compound e), two compound d, e are NKT cell advantages by biological test
Induce Th2 cytokines.And ours test result indicates that simply in α-GalCer analog sphingols chain 4,5 be changed to it is suitable
Formula, the induction of NKT cells advantage is not just Th2 cytokines, and is Th1 cytokines.It can be seen that cis double bond is changed
The space trend of sphingol chain, directly influences the stability of itself and CD1d combination, and then has influence on NKT and produce cell factor
Type.Also further illustrate, past conclusion is the NKT cells advantage induction Th2 when long-chain of the acid amides chain containing cis-double bonds
Cytokines, are incomplete;When α-GalCer analog sphingol chains have fine distinction, though α-GalCer analog acyls
Long-chain of the amine chain containing cis-double bonds but advantage induction be Th1 cytokines.Can tentative prediction cis-double bonds on sphingol chain
It is the deciding factor for having influence on the type that NKT produces cell factor.Because cell factor Th1 immune responses activation it is specific its
His immunocyte(B cell, T cell, macrophage etc.)To play antitumor, antibacterial functions, compound 1b, 1c tool tumour immunity is controlled
The application potential for the treatment of.
Beneficial effects of the present invention are as follows:
(1)Extend alpha-galactosylceramide Novel isomeric, 4,5 cis-double bonds sphingol chain derivatives of system research
Immunocompetence;(2)It was found that cis-double bonds influences on the immunocompetence of alpha-galactosylceramide Novel isomeric, i.e., in sphingol
In the case of the cis-double bonds of chain 4,5, changing acid amides chain has the cis-double bonds of different saturation;(3)New invention overcomes original technology
Middle KRN7000 produces Th1 the and Th2 type immune responses confronted with each other simultaneously, has obvious selection to the induction of NKT cells
Property, i.e., preferential NKT Th1 cell factors;(4)New invention overcomes KRN7000 further drawbacks in original technology to be overstimulation;
(5)From the internal test of the test of mouse source NKT hybridomas, the primary splenocyte test in mouse source to mouse living, the neural acyl of α-galactolipin
The activity of amine Novel isomeric is consistent, i.e., preferential induction NKT Th1 cell factors;Result is also particularly after experiment in vivo
It is very prominent, for alpha-galactosylceramide Novel isomeric is further provided reliable basis for immunization therapy;(6)Cross
The conclusion gone NKT cells advantage induction Th2 cytokines i.e. when long-chain of the acid amides chain containing cis-double bonds, are incomplete;
When α-GalCer analog sphingol chains have fine distinction, though long-chain of the α-GalCer analog acid amides chains containing cis-double bonds
Advantage induction is Th1 cytokines.Can tentative prediction cis-double bonds be on sphingol chain have influence on NKT produce cell factor
Type deciding factor.(7)Because alpha-galactosylceramide Novel isomeric preferentially induces NKT Th1 cell factors, exempt from
Other specific immunocytes of epidemic disease reacting activation(B cell, T cell, macrophage etc.), can be bright to play antitumor, antibacterial functions
Determine that alpha-galactosylceramide Novel isomeric 1c has the application potential of immunotherapy of tumors.
Brief description of the drawings
Fig. 1 is the structure and advantage inducing cytokine situation map for the alpha-galactosylceramide isomers reported;
Fig. 2 is the alpha-galactosylceramide Novel isomeric of the present invention(1a-1c)Structure chart;
Fig. 3 is active testing figure of the alpha-galactosylceramide Novel isomeric to mouse source NKT hybridomas 2H4;
Fig. 4 is active testing figure of the alpha-galactosylceramide Novel isomeric to mouse source NKT hybridomas 2Cl2;
Fig. 5 is cytokine induction figure of the α-galactosylceramide Novel isomeric to mouse source splenocyte;
Fig. 6 is α-galactosylceramide Novel isomeric in Mice Body based intracellular cvtokine induced map.
Embodiment
Technical scheme is elaborated with reference to specific embodiment:
Embodiment 1
Alpha-galactosylceramide Novel isomeric is detected to mouse source NKT hybridoma 2H4 and 2Cl2 immunocompetence
Experiment
1)The culture of cell
Mouse source NKT hydridization knurl and A20-CD1d cell lines are provided by Mitchell Kronenberg(La Jolla allergy
Reaction and immunological investigation institute, La Jolla, the U.S.).Cell line is stored in containing 10% hyclone, 2mM Sodium Pyruvates, 2nM
In the RPM1640 culture mediums of Pidolidone salt and 50 μM of 2 mercapto ethanols.
2)NKT hybridomas are determined
Recognize that glycolipid submission NKT hydridization knurls 2H4 secretes IL-2 by A20-CD1d.α-GalCer and the medicine for needing test
Thing is dissolved in DMSO(Dimethylformamide)In, concentration is 1mg/mL, and is diluted to required concentration with cell culture fluid, is then added to
A20-CD1d cells(105It is individual)Middle culture 16h, then washs A20-CD1d cells with nutrient solution, and thin with 2H4 hydridization knurls
Born of the same parents (5 × 104Cells) mix.Finally in mixture(200μL)Cultivate 24h, the IL-2 then discharged(pg/mL)Pass through enzyme
Linked immunosorbent assay.(Shanghai Excell Biology Product Co., Ltd., Shanghai, China).
NKT hydridization knurls 2Cl2 after the same method, the IL-2 of release(pg/mL)Pass through enzyme linked immunosorbent assay (ELISA).
As a result Fig. 3, Fig. 4 are seen.(the IL-2 discharged to NKT hybridomas(pg/mL)Carry out enzyme linked immunosorbent assay (ELISA).
Hybridoma cultivates 24h in 1 μ g/mL alpha-galactosylceramide Novel isomeric and 100ng/mL α-GalCer.Data
For the average value of three experiments.)
Embodiment 2
α-galactosylceramide Novel isomeric is to mouse source spleen lymphocyte stimulated in vitro
In order to further analyze the NKT derivants newly synthesized in Th1 and Th2 induced selective, surveyed in finite concentration
New synthesis molecule or blank in the case of culture mouse source spleen lymphocyte, a couple of days stimulate after collect cells and supernatant,
IFN-r in ELISA detection supernatants(Th1 cell factors)And IL-4(Th2 cell factors)Content.
1)Mouse source spleen lymphocyte testing in vitro
C57BL/6 mouse source spleen lymphocyte(5×105)In the α-GalCer containing 0.1 μ g/mL, finite concentration need to be surveyed
Cultivated five days in compound, or DMSO blank 96- holes U chassis, culture medium is to contain 10% FCS(Tire calf serum), L- paddy ammonia
The RPMI1640 culture mediums of hydrochlorate, 2 mercapto ethanol, penicillin and streptomysin.Temperature is 37 °C, carbonated 5%.And in training
Add 25 IU/mL mIL-2 PeproTech within foster second day(Growth factor).Acellular upper liquid is used as after collecting five days
Cytokine assay, and IFN-γ and IL-4 value pass through enzyme linked immunosorbent assay (ELISA).
2)Mouse source spleen lymphocyte testing in vitro result.
See Fig. 5.(certain density sample five days hatch after enzyme linked immunosorbent assay (ELISA) culture supernatant IFN-γ and
IL-4.Data are the average value for taking three experiments.)
Embodiment 3
Immunization experiment in the Mice Body of the C57BL of alpha-galactosylceramide Novel isomeric/6
1)The mouse experiment in vivo of alpha-galactosylceramide Novel isomeric
The μ g of alpha-galactosylceramide Novel isomeric 1 and the μ g of reference substance α-GalCer 1 are dissolved in 200 μ L PBS(I.e. phosphoric acid delays
Rush salting liquid)The mouse of C57BL/6 is injected intraperitoneally.2 serum collection points (2 h and 24 hours), to IFN-γ and IL-4
ELISA is determined.
2)Experimental result in the Mice Body of alpha-galactosylceramide Novel isomeric.
See Fig. 6.(Data are the average value of three experiments.)
(Funded projects:State natural sciences fund 30870553;National International Sci & Tech Cooperation project 2010DFA34370;
Zhejiang Province International Sci & Tech Cooperation special project 2013C14012.)
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all the present invention spirit and
Any modifications, equivalent substitutions and improvements made within principle etc., are all contained within protection scope of the present invention.
Claims (2)
1. a kind of application of alpha-galactosylceramide isomers in preferential induction Th1 Cytokines Drugs are prepared, the α-half
The sphingol chain of galactosylceramide isomers is with one or more cis double on 4,5 cis-double bonds sphingol chains, acyl chain
Key.
2. a kind of application of alpha-galactosylceramide isomers in tumour immunity medicine is prepared, the alpha-galactosylceramide
The sphingol chain of isomers is with one or more cis-double bonds on 4,5 cis-double bonds sphingol chains, acyl chain.
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CN109721510B (en) * | 2018-12-28 | 2021-03-23 | 浙江大学 | Ceramide analogue B and preparation method and application thereof |
CN111514264A (en) * | 2020-06-10 | 2020-08-11 | 云南中医药大学 | Application of fructus amomi residue extract in preparation of medicine for activating natural killer T cells |
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CN1279713A (en) * | 1997-09-22 | 2001-01-10 | 麒麟麦酒株式会社 | Cellular immunogenicity potentiating composition containing alpha-glycosylceramide |
CN101010086A (en) * | 2004-08-27 | 2007-08-01 | 耶希瓦大学艾伯塔·爱恩斯坦医学院 | Ceramide derivatives as modulators of immunity and autoimmunity |
CN102020685A (en) * | 2010-11-19 | 2011-04-20 | 浙江大学 | Alpha-glycosyl ceramide new isomer molecular structure and preparation method thereof |
CN104497064A (en) * | 2014-11-24 | 2015-04-08 | 浙江大学 | Alpha-galactosyl ceramide new isomer and synthetic method thereof |
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CN1279713A (en) * | 1997-09-22 | 2001-01-10 | 麒麟麦酒株式会社 | Cellular immunogenicity potentiating composition containing alpha-glycosylceramide |
CN101010086A (en) * | 2004-08-27 | 2007-08-01 | 耶希瓦大学艾伯塔·爱恩斯坦医学院 | Ceramide derivatives as modulators of immunity and autoimmunity |
CN102020685A (en) * | 2010-11-19 | 2011-04-20 | 浙江大学 | Alpha-glycosyl ceramide new isomer molecular structure and preparation method thereof |
CN104497064A (en) * | 2014-11-24 | 2015-04-08 | 浙江大学 | Alpha-galactosyl ceramide new isomer and synthetic method thereof |
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