CN103743910A - Application of CTBS (Di-N-acetylchitobiase) protein serving as target spot of sperm-egg binding acceptor to screening of sperm-egg binding inhibitor - Google Patents
Application of CTBS (Di-N-acetylchitobiase) protein serving as target spot of sperm-egg binding acceptor to screening of sperm-egg binding inhibitor Download PDFInfo
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Abstract
The invention relates to an application of a CTBS (Di-N-acetylchitobiase) protein serving as a target spot of a sperm-egg binding acceptor to screening of a sperm-egg binding inhibitor. According to the application, CTBS is a special sperm-egg binding acceptor on rodent sperm; the CTBS protein only has the specific expression on the sperms of rodents and the protein is not expressed on sperms of human beings; a CTBS antibody can inhibit the sperm-egg binding of mice. The screened sperm-egg binding acceptor is dequalinium chloride and the semi-inhibition constant is less than 100nM. The dequalinium chloride serves as fertility regulation medicine of the mice and the sperm-egg binding of the rodents can be effectively controlled, thus controlling the population quantity of the mice; the aim of controlling mouse damages without pesticides is realized; the damages are not caused when natural enemies of the mice eat the medicine.
Description
Technical field
The present invention relates to the application in the smart ovum binding inhibitors of screening as the target spot of smart ovum bind receptor of a kind of CTBS albumen.
Background technology
Dequalinium Chloride (Dequalinium chloride, CAS#522-51-0), as a kind of pkc inhibitor, as cancer therapy drug, use, its IC50 is 7-18 μ M, it is also a kind of selectivity apamin responsive type potassium-channel blocker simultaneously, and its IC50 is 1.1 μ M
[1,2,3,4].In recent years, Dequalinium Chloride is used for the antibacterials (medicine is called " dequaline chloride ") of non-antibiotic class as a kind of cationic surfactant.Recently, find that Dequalinium Chloride also can suppress the activity of microbe-derived chitin hydrolytic enzyme in nanomole level
[5].Dequalinium Chloride is very micro-to the toxicity of human body, does not affect the mankind's reproduction, and eye and skin are had to spread effect.To the lethal quantity of mouse, be: oral 150-1000mg/kg body weight, hypodermic injection 70mg/kg body weight, intravenous injection 1.9mg/kg body weight; To the oral lethal dose of rabbit and dog, be 500mg/kg body weight (MSDS).
And two-N-acetylchitobiose enzyme, Di-N-acetylchitobiase (being called for short CTBS) is a kind of of chitin hydrolytic enzyme, in mammal, only the liver in rodent and mankind's body has expression
[6,7,8].
The reproduction isolation of species is a kind of general spontaneous phenomenons, and on the carbohydrates on ovum oolemma and sperm, the interaction of protein is one of mechanism wherein.Have report to show, oligosaccharides Lewis X can be incorporated into mouse sperm, and can suppress specifically the in vitro fertilization of mouse, the fertility isolation of pointing out the albumen of identifying Lewis X on its sperm may participate in mouse
[9], but be only a kind of conjecture.
The plague of rats refers to the harm that muroid causes productions such as agriculturals.Muroid belongs to Mammalia (Mam-malia) grinding tooth day (Rodentia) animal, has kind more than 1600.Often, the pregnancy period is short in muroid breeding, and farrowing rate is high, and sexal maturity is fast, and quantity can sharply increase in a short time; Its adaptability is very strong, except Antarctica, on the ground all over the world, underground, tree, can survive in water, no matter huge disaster, so that desert area has its trace, is often led to productions such as agriculturals in Plain, high mountain, forest, grassland.
Therefore be badly in need of providing a kind of medicine that can control muroid fertility, especially suppress the inhibitor of the smart ovum combination of muroid, and this inhibitor can suppress the plague of rats in the wild and its natural enemy is edible harmless, without adopting agricultural chemicals to suppress the plague of rats.
List of references of the present invention is as follows:
ManettaA，et?al.Gynecol?Oncol，1993，50(1)，38-44。
Castle?NA，et?al.Eur?J?Pharmacol，1993，236(2)，201-207。
Dunn?PM，et?al.Eur?J?Pharmacol，1994，252(2)，189-194。
Rotenberg?SA，et?al.J?Biol?Chem，1998，273(4)，2390-2395。
Pantoom?S，et?al，J.Biol.Chem.2011，286∶24312-24323。
Aronson?NN?Jr，et?al，Arch?ofBiochem?Biophy,1989，272(2)，290-300。
Liu?B，et?al，Glycobiology,1999，9(6)，589-593。
Park?C，et?al，J?Biol?Chem2005，280，37204-37216。
Kerr?CL，et?al，Biol?Reprod，2004，71(3)，770-777。
Rao?FV,?et?al，Chem?Bio，2005，12，973-980。
Shur?BD，et?al，J?Biol?Chem1988,263，17706-17714。
Summary of the invention
The object of the present invention is to provide the application in the smart ovum binding inhibitors of screening as the target spot of smart ovum bind receptor of a kind of CTBS albumen, and screen a kind of Dequalinium Chloride inhibitor that can suppress the smart ovum combination of muroid, this inhibitor can be used for controlling the population quantity of muroid, thereby reach without adopting agricultural chemicals can control the effect of the plague of rats, and edible this medicine of the natural enemy of muroid is harmless.
To achieve these goals, the present invention adopts following technical scheme:
A kind of CTBS albumen is the application in the smart ovum binding inhibitors of screening as the target spot of smart ovum bind receptor.
Above-mentioned CTBS is two-N-acetylchitobiose enzyme, i.e. Di-N-acetylchitobiase, referred to as CTBS.
We find that CTBS is distinctive smart ovum bind receptor on rodent sperm after deliberation, and CTBS only expresses on the sperm of rodent, and CTBS antibody can suppress the inseminatio externalis of mouse, and on people's sperm, do not express this albumen.
The inhibitor Dequalinium Chloride obtaining through screening can suppress the in vitro fertilization of mouse effectively by suppressing the smart ovum combination of mouse, and very micro-to the toxic action of human body.Find after deliberation, described Dequalinium Chloride be described muroid smart ovum in conjunction with in specific expressed receptor protein CTBS inhibitor on sperm, CTBS be muroid smart ovum in conjunction with in requisite albumen, therefore the birth control medicine using Dequalinium Chloride as muroid is used, and Dequalinium Chloride can suppress the in vitro fertilization of mouse, the affinity that described inhibitor Dequalinium Chloride is combined with CTBS is strong, the activity of smart ovum combination that suppresses muroid is high, and what experiment showed that it suppresses smart ovum combination partly suppresses constant < 100nM; Further, its partly to suppress constant be 50nM.
Therefore, Dequalinium Chloride is as the birth control medicine of muroid, can be for controlling the population quantity of muroid, thus reach the object of controlling the plague of rats.
The present invention adopts CTBS albumen as the Sites Screening essence ovum binding inhibitors of smart ovum bind receptor, the Dequalinium Chloride obtaining through screening can effectively be controlled the smart ovum combination of rodent, reach the population quantity that controls muroid, realization can be controlled plague of rats object without agricultural chemicals, and edible this medicine of its natural enemy but can not produce harm.
Accompanying drawing explanation
Fig. 1 is the inhibition figure of Dequalinium Chloride to mouse in vitro fertilization.
Fig. 2 A is the evaluation thinking figure of Lewis X acceptor.
Fig. 2 B is the mouse sperm albumen figure that utilizes Lewis X probe to find.
Fig. 2 C is the mass spectrophotometry collection of illustrative plates of albumen.
Fig. 3 is the picture that the antibody suppression Lewis X of CTBS is attached to mouse sperm.
Fig. 4 is that the binding site of Lewis X on mouse sperm and CTBS are at the positioning result picture of mouse sperm.
Fig. 5 A is that interactional schematic diagram occurs people source CTBS and the Mouse Eggs oolemma of restructuring.
Fig. 5 B is that interactional light field and fluorescence photo occur people source CTBS and the Mouse Eggs oolemma of restructuring.
Fig. 5 C is RFP or the analysis of RFP-CTBS protein immunoblot that the latex particle of CTBS antibody is enriched to.
Fig. 6 is the inductive effect figure of CTBS Antibody on Mouse sperm acrosome reaction.
Fig. 7 is the figure in vitro fertilization of the CTBS antibody suppression mouse of variable concentrations.
Fig. 8 is the protein blot analysis chart of mouse, rat and people's sperm lysate.
Embodiment
By particular specific embodiment explanation embodiments of the present invention, person skilled in the art scholar can understand other advantages of the present invention and effect easily by the disclosed content of this instructions below.
Embodiment 1:
We find to express on the sperm of CTBS rodent through experiment, and CTBS antibody can suppress the inseminatio externalis of mouse, and on people's sperm, do not express this albumen.Its experimental technique is as follows:
(1) discovery of CTBS on mouse sperm:
Utilize lewis oligosaccharide X (be Lewis X, be abbreviated as LeX) probe to identify the CTBS on mouse sperm, and prove that CTBS can be incorporated into the ovum oolemma of mouse.
(1) first Lewis X acceptor is identified, its identity process as shown in Figure 2 A, comprises the identity process of the agglutinoid albumen that can identify Lewis X and the Identification of Fusion Protein flow process that the endogenic Lewis of containing X modifies.Its principle is that bovine serum albumin(BSA) (BSA) finishing Lewis X is made to Neoglycoproteins LeX-BSA, and this Neoglycoproteins is further modified to upper UV-crosslinked reagent [6-(biotin acylamino)-2-(p-azido benzoyl is amino) hexanoyl is amino] ethyl-1,3 '-bis-propane thioic acid sulfosuccinimide esters (Sulfo-NHS-2-(6-[biotinamido]-2-(p-azido benzamido)-hexanoamido) ethyl-1,3 '-dithiopropionate, is called for short Sulfo-SBED) as LewisX probe.This probe forms Lewis X probe-receptor complex through UV-crosslinked after mouse sperm, four rib lotus agglutinins (Lotus tetragonolobus agglutinin the is called for short LTA) resin that utilization can be identified Lewis X carrys out the Lewis X probe-receptor complex in separation and purification spermatoblast lysate.Owing to may containing the albumen of endogenous Lewis X modification in mouse sperm, the Identification of Fusion Protein flow process that is provided with the endogenic Lewis of containing X modification is distinguished this albuminoid (control group) in contrast.In general, the differential protein that two flow processs identify is likely the receptor protein of Lewis X.
(2) utilize the albumen on the mouse sperm that Lewis X probe finds:
Utilize Lewis X probe to find mouse sperm albumen, as shown in Figure 2 B.Differential band in Fig. 2 B 1,2,3,4 is taken off, for the Mass Spectrometric Identification of albumen, mass spectrophotometry figure as shown in Figure 2 C, by analysis, likely as shown in table 1 with the albumen identity of carbohydrates effect.
Table 1
Note: the first hurdle in table 1 is nucleocytoplasmic ratio, the second hurdle is peptide sequence, third column is protein identity.
(3) antibody capable of CTBS inhibition Lewis X-fluorescence probe is attached to mouse sperm:
Lewis X-fluorescence probe LeX-BSA-Alexa430 adds fluorophor Alexa430 by the Neoglycoproteins LeX-BSA of LewisX and is prepared from.As shown in Figure 3, this probe can be incorporated on the mature sperm that mouse epididymis afterbody takes out (positive control).Antibody is the rabbit polyclonal antibody of being prepared by the CTBS recombinant protein in people source, purchased from Wuhan Sanying Bio-Technology Co., Ltd..
Find after deliberation to only have the antibody capable inhibition LeX-BSA-Alexa430 of CTBS to be attached to mouse sperm, as shown in Figure 3.And a kind of weak chitinase inhibitors oxpentifylline (Pentoxifylline is called for short PTX) also can suppress this combination
[10], got rid of nonspecific combination that the space steric effect of antibody itself causes and suppressed.
(4) binding site of Lewis X on mouse sperm is consistent in the location of mouse sperm with CTBS:
Lewis X-fluorescence probe LeX-BSA-Alexa430 adds fluorophor Alexa430 by the Neoglycoproteins LeX-BSA of LewisX and is prepared from.This probe can be incorporated on the mature sperm of mouse epididymis afterbody taking-up, as shown in Fig. 4 illustration, consistent with previous report in conjunction with situation
[9].Antibody is the rabbit polyclonal antibody of being prepared by the CTBS recombinant protein in people source, purchased from Wuhan Sanying Bio-Technology Co., Ltd..By immunofluorescence, locate, we find that the binding site of LeX-BSA-Alexa430 on mouse sperm is consistent with the CTBS protein localization of mouse sperm, as shown in Figure 4.
(5) interaction that the people source CTBS (being rCTBS) of restructuring and Mouse Eggs oolemma (ZP) occur:
A. experimental considerations as shown in Figure 5A, is fixed to red fluorescent protein (RFP) antibody on latex particle, and the restructuring RFP-CTBS protein enrichment that is expressed in 293 cells, to latex particle, and is added in the nutrient culture media of Mouse Eggs.If CTBS can identify the carbohydrates on Mouse Eggs oolemma, on mouse oolemma by the latex particle of sclerozone red fluorescence.
B. Fig. 5 B is light field (left side) and red fluorescence (right side) photo.Found that the latex particle that is only enriched to RFP cannot be attached on the ovum oolemma of mouse (as shown in Fig. 5 B lastrow); And with the latex particle of RFP-CTBS, can be incorporated on the ovum oolemma of mouse (as shown in Fig. 5 B middle row), CTBS antibody can hinder this in conjunction with (as shown in Fig. 5 B next line).The fluorescence photo on right side has confirmed above-mentioned observation.
C. Fig. 5 C is western blot analysis result, illustrates result and shows, the latex particle that is combined with RFP antibody can enrichment RFP or RFP-CTBS.Wherein white arrow refers to RFP, and black arrow refers to RFP-CTBS.
The above results has proved that the people source CTBS of restructuring can interact with Mouse Eggs oolemma.
(2) CTBS has participated in the fertilization process of mouse.
(1) inductive effect of CTBS Antibody on Mouse sperm acrosome reaction:
Adopt the acrosome reaction of the CTBS antibody induction mouse sperm of variable concentrations between 0-30ug/ml, as shown in Figure 6, result proof CTBS antibody can inducing mouse sperm acrosome reaction, the feature that on this mouse sperm of reporting with prior art, smart ovum shows in conjunction with relevant receptor protein is consistent
[11].
(2) the CTBS antibody suppression mouse of variable concentrations is in vitro fertilization:
Adopt CTBS antibody suppression mouse in vitro fertilization of variable concentrations, as shown in Figure 7, result proof CTBS antibody capable well suppresses the in vitro fertilization of mouse, further show CTBS on mouse sperm really with the smart ovum of mouse in conjunction with relevant.
(3) the protein blot analysis of mouse, rat and people's sperm lysate.
Sperm lysate to mouse, rat and people carries out protein blot analysis, and the applied sample amount of sperm lysate is mouse 50ug, rat 60ug, people 60ug.Antibody is the rabbit polyclonal antibody of being prepared by the CTBS recombinant protein in people source, purchased from Wuhan Sanying Bio-Technology Co., Ltd.; The applied sample amount of human cell line Hela cell pyrolysis liquid is 10ug; Use Alpha's one tubulin (α-tubulin) as the reference of albumen applied sample amount.Result as shown in Figure 8, shows that the CTBS in CTBS antibody on human source has very high sensitivity, has further proved that CTBS does not express on people's sperm, and only on the sperm of rodent, has had expression.
Embodiment 2: Dequalinium Chloride is as the inhibitors experiment that suppresses the combination of mouse essence ovum
Using Dequalinium Chloride as the inhibitor that suppresses the combination of mouse essence ovum, adopt 50 of the mouse eggs > for each dosage experiments of CTBS variable concentrations, repeat 3 times, each dosage amounts to 150 of ovum >, its experimental result as shown in Figure 1, it partly suppresses constant at 50nM, shows that Dequalinium Chloride can well suppress the in vitro fertilization of mouse.
To sum up all results described in embodiment 1 and embodiment 2 show, CTBS is receptor protein specific expressed on rodent sperm, and it has participated in the physiology course of smart ovum combination, and CTBS antibody capable suppresses the in vitro fertilization of mouse.Dequalinium Chloride can well suppress the in vitro fertilization of mouse as the birth control medicine of muroid, and experiment shows that it partly suppresses constant at 50nM.
Above-described embodiment is illustrative principle of the present invention and effect thereof only, but not for limiting the present invention.Any person skilled in the art scholar all can, under spirit of the present invention and category, modify or change above-described embodiment.Therefore, such as in affiliated technical field, have and conventionally know that the knowledgeable, not departing from all equivalence modifications that complete under disclosed spirit and technological thought or changing, must be contained by claim of the present invention.
Claims (4)
1.CTBS albumen is the application in the smart ovum binding inhibitors of screening as the target spot of smart ovum bind receptor.
2. CTBS albumen as claimed in claim 1 application in the smart ovum binding inhibitors of screening as the target spot of smart ovum bind receptor, it is characterized in that, CTBS is distinctive smart ovum bind receptor on rodent sperm, CTBS albumen only has specific expressed on the sperm of rodent, on people's sperm, do not express this albumen, and CTBS antibody capable suppresses the smart ovum combination of mouse.
3. CTBS albumen as claimed in claim 1 or 2 application in the smart ovum binding inhibitors of screening as the target spot of smart ovum bind receptor, is characterized in that, the smart ovum binding inhibitors screening is Dequalinium Chloride; Described Dequalinium Chloride be described muroid smart ovum in conjunction with in the inhibitor of specific expressed receptor protein CTBS on sperm.
4. CTBS albumen as claimed in claim 3 application in the smart ovum binding inhibitors of screening as the target spot of smart ovum bind receptor, is characterized in that, what described Dequalinium Chloride suppressed the combination of muroid essence ovum partly suppresses constant < 100nM.
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Citations (5)
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| CN1136778A (en) * | 1993-12-10 | 1996-11-27 | 查珀尔希尔北卡罗来纳大学 | Sperm antigen corresponding to sperm zone binding protein autoantigenic epitope |
| CN1643148A (en) * | 2002-02-14 | 2005-07-20 | 独立行政法人科学技术振兴机构 | Mouse spermatogenesis genes, human male sterility-associated genes and diagnostic system using the same |
| US20050260664A1 (en) * | 2004-05-21 | 2005-11-24 | Shaughnessy John D | Use of gene expression profiling to predict survival in cancer patient |
| WO2006111706A1 (en) * | 2005-04-16 | 2006-10-26 | Axordia Limited | Cytotrophoblast stem cell |
| CN101086809A (en) * | 2006-06-05 | 2007-12-12 | 中国医学科学院基础医学研究所 | An animal model for studying sperm generation |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1136778A (en) * | 1993-12-10 | 1996-11-27 | 查珀尔希尔北卡罗来纳大学 | Sperm antigen corresponding to sperm zone binding protein autoantigenic epitope |
| CN1643148A (en) * | 2002-02-14 | 2005-07-20 | 独立行政法人科学技术振兴机构 | Mouse spermatogenesis genes, human male sterility-associated genes and diagnostic system using the same |
| US20050260664A1 (en) * | 2004-05-21 | 2005-11-24 | Shaughnessy John D | Use of gene expression profiling to predict survival in cancer patient |
| WO2006111706A1 (en) * | 2005-04-16 | 2006-10-26 | Axordia Limited | Cytotrophoblast stem cell |
| CN101086809A (en) * | 2006-06-05 | 2007-12-12 | 中国医学科学院基础医学研究所 | An animal model for studying sperm generation |
Non-Patent Citations (2)
| Title |
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| 周密: "精卵结合分子机制的研究进展", 《中国男科学杂志》, vol. 21, no. 12, 31 December 2007 (2007-12-31), pages 67 - 71 * |
| 彭南妮等: "卵巢移植对雄性受体鼠精子及生殖能力的影响", 《湖南农业大学学报（自然科学版）》, vol. 36, no. 1, 28 February 2010 (2010-02-28), pages 73 - 76 * |
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