KR101650778B1 - Peptide analog binding to polo-box domain of polo-like kinase-1 and pharmaceutical composition for contraception containing thereof - Google Patents

Abstract

The present invention relates to a novel peptide analogue, or a stereoisomer or pharmaceutically acceptable salt thereof, and more particularly to a novel peptide analogue, or a stereoisomer or a pharmaceutically acceptable salt thereof, which contains the novel peptide analogue or a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient ≪ / RTI > The novel peptide analogue, or a stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that it specifically binds to the poloxane domain of polo-like phosphorylase-1 and is characterized by inhibiting oocyte maturation, It can be utilized as a composition.

Description

[0001] The present invention relates to a peptide analogue that specifically binds to the polo box domain of polo-like phosphorylase-1 and a composition comprising the peptide analogue as an active ingredient. thereof}

The present invention relates to novel peptide analogs, or stereoisomers or pharmaceutically acceptable salts thereof, and uses thereof. More specifically, the present invention relates to a novel peptide analogue, or a stereoisomer or pharmaceutically acceptable salt thereof, and a contraceptive use thereof.

There are many contraceptive methods currently in use, including physical methods such as condoms and pemidomas, inhibition of ovulation by hormone preparations, administration of spermicides, and intrauterine devices. However, each method has specific disadvantages. For example, the reproductive cycle method has a high probability of failure, there is a sense of heterogeneity caused by condoms and femidomas, the risk of inflammation or pain in intrauterine devices, Hormone preparations are at risk of clots and menstrual irregularities. In particular, in the case of hormone preparations, administration of hormones for contraception causes other side effects (menstrual irregularities, bleeding, thrombosis, etc.) although the purpose of contraception is met. In the case of surgery for permanent contraception, there is the burden of the operation itself and the high cost of rebuilding. Therefore, considering the physiological, psychological burden and cost of the patients among the contravention methods so far, perfect contraceptive methods are nothing but abstinence.

Thus, the present inventors synthesized novel peptide analogs selectively binding to the poloxane domain based on the structure of emi2, a protein selectively binding to the poloxane domain of polo-like phosphorylase-1 in the meiosis process.

Polol-like phosphorylase-1 is a key regulator involved in both maturation and fertilization of oocytes, such as the maturation of cumulus cells into the oocyte and the resumption of meiosis after spermatogenesis. The activity of polo-like phosphorylase-1 Can inhibit the maturation of cumulus cells and the resumption of meiosis after fertilization, which ultimately can be used as an effective contraceptive.

Korean Patent Publication No. 10-2012-0044307

It is therefore an object of the present invention to provide a novel peptide analogue which specifically binds to the polo box domain of polo-like kinase-1.

Another object of the present invention is to provide a composition for pacing comprising the novel peptide analogue or a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for screening a contraceptive.

In order to achieve the object of the present invention as described above, the present invention provides a novel peptide analogue that specifically binds to the poloxane domain of polo-like phosphorylase-1, and the novel peptide analogue, or a stereoisomer thereof or a drug And a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the polo box domain of polo-like phosphorylase-1 may comprise the amino acid sequence of SEQ ID NO: 1.

In one embodiment of the invention, the phosphorylated peptide binding site is selected from the group consisting of 414 tryptophan, 415 valine, 416 aspartic acid, 417 tyrosine residues of the poloxane domain protein of polo-like phosphorylase-1 consisting of the amino acid sequence of SEQ ID NO: , The 481th tyrosine, and the 485th tyrosine.

In one embodiment of the present invention, the composition for parenteral administration may contain a novel peptide analogue, or a stereoisomer or a pharmaceutically acceptable salt thereof, at a concentration of 1 to 500 μM.

In one embodiment of the present invention, the patch composition may inhibit oocyte maturation.

Injecting a compound into an immature oocyte of a mammal in vitro; Injecting a contraceptive candidate into the immature oocyte; Inducing the in vitro maturation of immature oocytes; And measuring the degree of extracellular maturation.

In one embodiment of the present invention, a compound is injected into an immature oocyte of a mammal in a test tube, and the group in which the contraceptive candidate substance is injected into the immature oocyte and the group in which the contraceptive candidate substance is not injected are compared, And determining the candidate substance as a new contraceptive agent when the degree of extracellular maturation is further reduced in the injected group.

The novel peptide analogue or its stereoisomer or pharmaceutically acceptable salt of the present invention can be used as a composition for parenteral administration because it exhibits an excellent contraceptive effect through a mechanism of inhibiting maturation of the oocyte and the like.

Fig. 1 shows the nomenclature of the novel peptide derivatives synthesized in the present invention according to substituents.
Fig. 2 shows a structure in which a peptide analogue is combined with polo-like phosphorylase-1.
FIG. 3 is a schematic diagram of a method for verifying the inhibitory effect of oocyte maturation upon the introduction of a peptide analog into immature oocytes.
FIG. 4 is a graph showing the maturation inhibition rate of immature oocytes from pigs according to the injection of peptide analogs.
FIG. 5 is a graph showing the degree of inhibition of immature oocyte maturation by injection of the peptide analogue AB103-8.
6 is a photograph showing inhibition of nuclear decay by injection of the peptide analog AB103-8.
7 is a graph showing the effect of AB103-8 compounds on pathogenogenetic activation of mice.
8 is a photograph showing the state of mouse oocyte 3 hours after initiation of unit development of a mouse.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention provides a novel peptide analogue having the structure of the following formula (1).

[Chemical Formula 1]

In the above formula (1), R is

. ≪ / RTI >

The novel peptide analogues provided herein may comprise stereoisomers or salts, preferably pharmaceutically acceptable salts, having the structure of Formula 1 above. The pharmaceutically acceptable salts refer to salts suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation and side effects, etc., within the purview of pure medical judgment. Such pharmaceutically acceptable salts are well known in the art (SM Berge et al ., 1977, J. Parmaceutical Sciences , 66: 1). The salt may be prepared in the same reaction system during the final isolation, purification and synthesis of the derivative compound of the present invention, or separately, by reacting with an inorganic base or an organic base. As the pharmaceutically acceptable salt, when the derivative compound of the present invention contains an acidic group, it may form a salt with a base. Such salts include, for example, a lithium salt, a sodium salt, Salts with alkali metals such as potassium salts; Salts with alkaline earth metals such as barium or calcium; Salts with other metals such as magnesium salts; Organic base salts such as salts with dicyclohexylamine; And salts with basic amino acids such as lysine or arginine. In addition, when the derivative compound of the present invention contains a basic group in the molecule, an acid addition salt can be formed. Examples of such an acid addition salt include, but are not limited to, inorganic acids such as hydrohalic acid , Hydroiodic acid or hydrochloric acid), salts with nitric acid, carbonic acid, sulfuric acid or phosphoric acid; Salts with lower alkylsulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; Salts with benzenesulfonic acid or p-toluenesulfonic acid; Salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; And salts with amino acids such as glutamic acid or aspartic acid.

On the other hand, the mammalian oocyte is matured in the cumulus cell state and becomes fertile oocyte. The first meiosis state is maintained until fertilization, and the second fertilization progresses after fertilization. Or if such a process is inhibited or inhibited, eventually it becomes impossible to generate an individual. Metaphase promoting factor (MPF) is the main factor controlling oocyte maturation (Heinkiheimo et al., 1998). MPF is a dimer composed of Cyclin Dependent Kinase 1 (Cdk1) and Cyclin B (Cyclin B), which phosphorylate serine and threonine residues of a number of proteins. The activity of MPF in the oocyte is mainly controlled by the degradation of the cyclin B by the ubiquitin-dependent proteolytic pathway.

The protein involved in this process is Emi2, which is a protein specifically involved in the transition from the first meiosis to the second meiosis after fertilization. Emi2 inhibits this activity by binding to APC / C, a protein complex that binds ubiquitin in response to cyclin B and the like. It has been known that the calcium concentration is increased after the oocyte is modified by spermatozoa. The increased calcium concentration activates Calmodulin dependent kinase and the calmodulin-dependent kinase activates the 176th of Emi2 (Hansen et al, 2006). Phosphorylated emi2 is recognized by polo-like phosphorylase-1, is additionally phosphorylated, and phosphorylated emi2 is ultimately degraded by the ubiquitin-dependent proteolytic pathway, which is known to induce activation of APC / C and degradation of cyclin B (Shisako et al, 2006).

In addition, polo-like phosphorylase-1 plays a crucial role in the formation of the spindle in addition to the degradation of Emi2. In previous studies, polo-like phosphorylase-1 was inhibited by the injection of a specific antibody to polo-like phosphorylase-1 It has been reported that the process of maturation of cumulus cells is inhibited.

The polo-like phosphorylase-1 is a protein consisting of a kinase domain located at the N-terminus of the protein and a pollo-box domain located at the C-terminus. The kinase domain phosphorylates the serine or threonine of the target protein, It recognizes the target protein that contains threonine. The novel peptide analogues provided in the present invention are characterized by specific binding to the polo box domain of polo-like phosphorylase-1, and the contraceptive effect can be derived through a mechanism that inhibits the maturation of the oocyte.

More specifically, the pollo-box domain region of polo-like phosphorylase-1 to which the novel peptide analogue of the present invention can bind includes the 414th tryptophan in the amino acid sequence of pololo-like phosphorylase-1 protein shown in SEQ ID NO: 1, the 415th valine , The 416th aspartic acid, the 417th tyrosine, the 481th tyrosine, and the 485th tyrosine. The polo box domain of polo-like phosphorylase-1 may be composed of the amino acid sequence shown in SEQ ID NO: 1, and the amino acid sequence of SEQ ID NO: 1 is encoded by the nucleotide sequence shown in SEQ ID NO: 2. In addition, the novel peptide analogues provided in the present invention exist in the form of a complex in which a peptide and a compound are bonded to each other, and the specific chemical structural formula thereof is as described above.

The novel peptide analogue, which is an active ingredient contained in the composition of the present invention, may be contained in the composition at a concentration of 1 to 500 μM, but if it is out of this range, the desired effect may not be obtained.

In other words, when the concentration is less than 1 μM, the inhibitory activity against oocyte maturation may be insufficient. On the other hand, when the concentration exceeds 500 μM, the effect of 500 μM treatment can not be obtained. have. Therefore, it is preferable to contain it within the above-described range.

 Furthermore, the present invention can provide a method for inducing contraception by inhibiting oocyte maturation of a mammal using the novel peptide analogue provided in the present invention, and can also provide a method for screening a new contraceptive.

Specifically, the screening method comprises: injecting the peptide analog of claim 1 into an immature oocyte of a mammal in vitro; Injecting a contraceptive candidate into the immature oocyte; Inducing the in vitro maturation of immature oocytes; And measuring the degree of extracellular maturation.

Also, the process of determining that the contraceptive candidate substance can be used as a contraceptive in the above method includes a step of injecting a novel peptide analogue according to the present invention into an immature oocyte of a mammal in a test tube, injecting a contraceptive candidate substance into the immature oocyte, The candidate substance can be judged as a new contraceptive agent when the degree of extracellular maturation is decreased in the group injected with the contraceptive candidate substance compared with the group in which the contraceptive candidate substance is not injected, It can be seen as a substance that can promote and improve.

In addition, the method of measuring the degree of maturation of the oocyte in the above method can be analyzed by measuring the maturation rate of the oocyte. In the case of the mature oocyte of the pig, 44 hours after the initiation of extracellular maturation, The first polar body is normally released after 12 hours from the initiation of extracellular maturation. The oocyte maturation rate and the maturation inhibition rate are defined by the following formula.

Maturity rate (%) = [number of matured oocytes] / [total number of oocytes survived 6 hours after microinjection] x 100

Maturity inhibition rate (%) = 100 - Maturation rate of oocytes

The synthesis process for the novel compounds provided by the present invention and their activities will be described in more detail by way of the following examples. However, these examples are intended to further illustrate the present invention, and the scope of the present invention is not limited to these examples.

< Example  1>

Novel compounds having contraceptive activity ( Peptides  Synthesis of

The present inventors used Rink amide resin loaded at 0.61 mmol / g to synthesize the peptide analog of the present invention and synthesized by Fmoc (Fluorenylmethyloxycarbonyl) Solid Phase Peptide Synthesis (SPPS). Before the synthesis, the resin was swollen in N, N-dimethylforamide (DMF) for 45 minutes. To extend the peptide sequence, the Fmoc amino acid and the benzoic acid derivative corresponding to the amino acid and the aromatic derivative were dissolved in 2 ml of DMF solution (1-O-Benzotriazole-N, N ', N'-tetramethyluronium, HBTU) (5.0 g of benzotriazole-N, N, N'N'-tetramethyluronium hexafluorophosphate eq), 1-hydroxybenzotriazole (HOBt) (5.0 eq) and N, N-diisopropylethylamine (DIEA) (10.0 eq) And then activated for 2 minutes.

Then, the activated solution was mixed with the resin and the binding reaction was performed for 1 hour. After washing the resin with DMF, the Fmoc protecting group was removed by 20% piperidine in DMF. The resin was then washed again and then reacted with Fmoc-protected amino acids according to their respective amino acid sequences. After synthesis of the entire amino acid sequence was completed, the resin was washed with DMF, methanol, dichloromethane and ether and then dried in vacuo. The synthesized peptides were separated from the resin using 5% triisopropylsilane (TIS) and trifluoroacetic acid (TFA) containing 5% water. Peptide analogs isolated from the resin were precipitated with cold ether and then filtered. The peptide was then purified by reverse-phase (RP) HPLC using a Vydac _C18 column. The purity of the peptide was measured by reversed-phase HPLC and the molecular weight of the final peptide was measured by MALDI-TOF MS (Molecular-assisted laser desorption ionization-time-of-flight mass spectrometry) and the peptide derivative according to the benzoic acid derivative used As shown in Fig.

The analogs in Figure 1 were synthesized using the above method. However, the last residue analogs used the compounds described below instead of Fmoc-beta-Ala-OH. Benzoic acid for AB103, 6-hydroxy-2-naphthoic acid for AB113, naphthalene-1,4-dicarboxylic acid for AB112, 1,4-dicarboxylic acid, pentanoic acid in the case of AB116, cyclohexanecarboxylic acid in the case of AB103-1, 4-propylcyclohexanecarboxylic acid in the case of AB103-2 (4-propylcyclohexanecarboxylic acid) for AB103-6, 4-propoxycyclohexanecarboxylic acid for AB103-6, 4- (methylsulfonyl) benzoic acid for AB103-10 benzoic acid, 4-aminobutanoic acid in the case of AB103-15, 4- (methylamino) benzoic acid in the case of AB103-8, 4- 4-bromo-2-chlorobenzoic acid in the case of AB10700, 2-bromo-4-fluorobenzoic acid in the case of AB10700, 4-bromo-benzoic acid in the case of AB10701, 3-bromo-4-methoxybenzoic acid in the case of AB10702, AB10703 3,5-bis (trifluoromethyl) benzoic acid in the case of AB10704, 4-methoxybenzoic acid in the case of AB10704 and 3,5-bis (trifluoromethyl) benzoic acid in the case of AB10705 4-bromo-3,5-dimethoxybenzoic acid in the case of AB10706, 3-bromo-5-nitrobenzoic acid in the case of AB10706, , 4-chloro-3,5-dinitrobenzoic acid for AB10707, AB10708 for [1,1'-bisphenyl] -4-carboxylic acid ([ , 1'-biphenyl] -4-carboxylic acid.

< Example  2>

Peptides  Measurements of oocyte maturation inhibitory activity of analogues

In order to examine the inhibitory effect of the synthesized peptide analogues on the oocyte maturation, the peptide analogs were injected into the pig and mouse immature cells using the microinjection method, and then the injection of the compounds was performed to evaluate the efficiency of in vitro maturation (Figure 3). &Lt; RTI ID = 0.0 &gt;

<2-1> Pig Immature  Measurement used

First, porcine ovaries purchased from slaughterhouses were transported at 37 ° C under physiological saline. The oocyte-cumulus complex (Cumulus oocyte complex) was then inhaled from the ovary using an 18 gauge syringe. Then, a peptide at a concentration of 300 μM dissolved in 10% dimethylsulfoxide (DMSO) is injected at 5 to 10 μl using a microinjector (Femtojet, Eppendorf). The injected porcine oocyte-cumulus cell complex was treated with 0.1% polyvinyl alcohol, 3.05 mM D-glucose, 0.91 mM sodium pyruvate, 0.57 mM cysteine, 10 ng / ml epithelial cell growth factor (TCC-199 medium containing Epidermal Growth Factor), 10 IU / ml PMSG (Pregnant Mare Serum Gonadotropin), 10 IU / ml hCG (Human Chronic Gonadotropin), 75 mg / ml penicillin G and 50 mg / ml streptomycin 38.5 캜 and 5% carbon dioxide. The oocyte maturation inhibition rate of the peptides was then calculated as a percentage of the matured oocytes in which the first polar body was released for the entire microinjected oocyte.

As a control compound, Bg34, a control compound containing threonine that is not threonine phosphorylated, was microinjected, indicating that 109 eggs were successfully matured in a total of 135 eggs, whereas 19 eggs (26 / 135), respectively.

On the other hand, when the compound of the formula (I) is a compound (20%), 31% (14/44), 33% (7/21), 70% (14/20), 47% (51/108) and 35% , 23% (4/17), 16% (7/42), 13% (6/43), 32% (12/37), 66% (22/33), 37% (27/51), 55% (11/20), 32% (8/25), 20% (5/24), 38% (14/37), 52% (17/33), 54% 14/26) and 54% (21/39), respectively. (Fig. 4)

<2-2> Immature  Measurement used

First, 5 units of PMSG (Pregnant Mare Serum Gonadotropin) were injected into ICR (Imprinting Control Region) mice at 6-8 weeks of age to induce superovulation, and oocytes were collected from the ovaries. In the same manner as in <2-1> above, the peptide at a concentration of 300 μM dissolved in 10% dimethylsulfoxide (DMSO) was injected with 5-10 μl using a microinjector (Femtojet, Eppendorf) (Sigma) at 37 ° C for 16 hours, and the inhibition rate of oocyte maturation of the peptide was calculated according to whether the first polar body was released or not.

The analysis showed that polar excretion was inhibited in 20% of oocytes (11/51) in the control group while polar excretion was inhibited in 60% (61/99) of oocytes (Fig. 5). The nucleus and spindle of the oocyte were stained by immunofluorescence staining and observed with a scanning confocal microscope. As a result, it was confirmed that maturity was inhibited in the oocyte microinjected with AB103-8 compound without occurrence of germinal vesicle breakdown 6).

< Example  3>

Unit Generation pathernogenetic activation )On by Peptides  Measurement of oocyte fertilization activity of analogues

In order to measure the inhibitory activity of oocyte, unit induction by strontium chloride (SrCl ₂ ) was performed. 5 units of PMSG and 5 units of hCG were injected from mice (B6D2F1) and mature oocytes were collected 48 hours after induction of superovulation. Thereafter, the peptide at a concentration of 300 μM dissolved in 10% dimethylsulfoxide (DMSO) was injected with 5-10 μl using a microinjector (Femtojet, Eppendorf), and then cultured in CZM medium for 2 hours. After that, 2 mM EGTA (Ethylene Glycol Tetraacetic Acid) and 5 mM strontium chloride (SrCl ₂ ) were added to induce the unit generation, and the second polar body emission was observed by reversed phase microscopy at 1 hour intervals.

As a result, as shown in FIG. 6, the control group, DMSO injected group, did not differ from the non-injected group, whereas the AB103-8 compound injected group showed delayed second polar body emission. The nucleus and spindle of the oocyte were stained with immunofluorescence staining and observed with a scanning confocal microscope. As a result, it was confirmed that maturation was inhibited in the oocyte microinjected with AB103-8 compound without occurrence of germinal vesicle breakdown 8).

As described in the above examples, it was found that the novel peptide analogs synthesized by the present inventors can be used to inhibit the maturation of oocytes. Thus, it was confirmed that the novel peptide analogue can be used as a composition for parenteral administration.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

<110> Chungbuk National University Industry-Academic Cooperation Foundation <120> Peptide analog binding to polo-box domain of polo-like kinase-1          and pharmaceutical composition for contrast          the <130> PN1409-271 <160> 2 <170> Kopatentin 2.0 <210> 1 <211> 603 <212> PRT <213> Mus musculus <400> 1 Met Asn Ala Ala Ala Lys Ala Gly Lys Leu Ala Arg Ala Pro Ala Asp   1 5 10 15 Leu Gly Lys Gly Gly Val Pro Gly Asp Ala Val Pro Gly Ala Pro Val              20 25 30 Ala Ala Pro Leu Ala Lys Glu Ile Pro Glu Val Leu Val Asp Pro Arg          35 40 45 Ser Arg Arg Gln Tyr Val Arg Gly Arg Phe Leu Gly Lys Gly Gly Phe      50 55 60 Ala Lys Cys Phe Glu Ile Ser Asp Ala Asp Thr Lys Glu Val Phe Ala  65 70 75 80 Gly Lys Ile Val Pro Lys Ser Leu Leu Leu Lys Pro His Gln Lys Glu                  85 90 95 Lys Met Ser Met Glu Ile Ser Ile His Arg Ser Leu Ala His Gln His             100 105 110 Val Val Gly Phe His Asp Phe Phe Glu Asp Ser Asp Phe Val Phe Val         115 120 125 Val Leu Glu Leu Cys Arg Arg Arg Ser Leu Leu Glu Leu His Lys Arg     130 135 140 Arg Lys Ala Leu Thr Glu Pro Glu Ala Arg Tyr Tyr Leu Arg Gln Ile 145 150 155 160 Val Leu Gly Cys Gln Tyr Leu His Arg Asn Gln Val Ile His Arg Asp                 165 170 175 Leu Lys Leu Gly Asn Leu Phe Leu Asn Glu Asp Leu Glu Val Lys Ile             180 185 190 Gly Asp Phe Gly Leu Ala Thr Lys Val Glu Tyr Glu Gly Glu Arg Lys         195 200 205 Lys Thr Leu Cys Gly Thr Pro Asn Tyr Ile Ala Pro Glu Val Leu Ser     210 215 220 Lys Lys Gly His Ser Phe Glu Val Asp Val Trp Ser Ile Gly Cys Ile 225 230 235 240 Met Tyr Thr Leu Leu Val Gly Lys Pro Pro Phe Glu Thr Ser Cys Leu                 245 250 255 Lys Glu Thr Tyr Leu Arg Ile Lys Lys Asn Glu Tyr Ser Ile Pro Lys             260 265 270 His Ile Asn Pro Val Ala Ala Ser Leu Ile Gln Lys Met Leu Gln Thr         275 280 285 Asp Pro Thr Ala Arg Pro Thr Ile His Glu Leu Leu Asn Asp Glu Phe     290 295 300 Phe Thr Ser Gly Tyr Ile Pro Ala Arg Leu Pro Ile Thr Cys Leu Thr 305 310 315 320 Ile Pro Pro Arg Phe Ser Ile Ala Pro Ser Ser Leu Asp Pro Ser Ser                 325 330 335 Arg Lys Pro Leu Lys Val Leu Asn Lys Gly Val Glu Asn Pro Leu Pro             340 345 350 Asp Arg Pro Arg Glu Lys Glu Glu Pro Val Val Arg Glu Thr Asn Glu         355 360 365 Ala Ile Glu Cys His Leu Ser Asp Leu Leu Gln Gln Leu Thr Ser Val     370 375 380 Asn Ala Ser Lys Pro Ser Glu Arg Gly Leu Val Arg Gln Glu Glu Ala 385 390 395 400 Glu Asp Pro Ala Cys Ile Pro Ile Phe Trp Val Ser Lys Trp Val Asp                 405 410 415 Tyr Ser Asp Lys Tyr Gly Leu Gly Tyr Gln Leu Cys Asp Asn Ser Val             420 425 430 Gly Val Leu Phe Asn Asp Ser Thr Arg Leu Ile Leu Tyr Asn Asp Gly         435 440 445 Asp Ser Leu Gln Tyr Ile Glu Arg Asp Gly Thr Glu Ser Tyr Leu Thr     450 455 460 Val Ser Ser His Pro Asn Ser Leu Met Lys Lys Ile Thr Leu Leu Asn 465 470 475 480 Tyr Phe Arg Asn Tyr Met Ser Glu His Leu Leu Lys Ala Gly Ala Asn                 485 490 495 Ile Thr Pro Arg Glu Gly Asp Glu Leu Ala Arg Leu Pro Tyr Leu Arg             500 505 510 Thr Trp Phe Arg Thr Arg Ser Ale Ile Ile Leu His Leu Ser Asn Gly         515 520 525 Thr Val Gln Ile Asn Phe Phe Gln Asp His Thr Lys Leu Ile Leu Cys     530 535 540 Pro Leu Met Ala Ala Val Thr Tyr Ile Asn Glu Lys Arg Asp Phe Gln 545 550 555 560 Thr Tyr Arg Leu Ser Leu Leu Glu Glu Tyr Gly Cys Cys Lys Glu Leu                 565 570 575 Ala Ser Arg Leu Arg Tyr Ala Arg Thr Met Val Asp Lys Leu Leu Ser             580 585 590 Ser Arg Ser Ala Ser Asn Arg Leu Lys Ala Ser         595 600 <210> 2 <211> 1812 <212> RNA <213> Homo sapiens <400> 2 atgagtgctg cagtgactgc agggaagctg gcacgggcac cggccgaccc tgggaaagcc 60 ggggtccccg gagttgcagc tcccggagct ccggcggcgg ctccaccggc gaaagagatc 120 ccggaggtcc tagtggaccc acgcagccgg cggcgctatg tgcggggccg ctttttgggc 180 aagggcggct ttgccaagtg cttcgagatc tcggacgcgg acaccaagga ggtgttcgcg 240 ggcaagattg tgcctaagtc tctgctgctc aagccgcacc agagggagaa gatgtccatg 300 cggctttttc gaggacaacg acttcgtgtt cgtggtgttg gagctctgcc gccggaggtc tctcctggag 420 ctgcacaaga ggaggaaagc cctgactgag cctgaggccc gatactacct acggcaaatt 480 gtgcttggct gccagtacct gcaccgaaac cgagttattc atcgagacct caagctgggc 540 aaccttttcc tgaatgaaga tctggaggtg aaaatagggg attttggact ggcaaccaaa 600 gtcgaatatg acgggagag gaagaagacc ctgtgtggga ctcctaatta catagctccc 660 gaggtgctg gcaagaaagg gcacagtttc gaggtggatg tgtggtccat tgggtgtatc 720 atgtatacct tgttagtggg caaaccacct tttgagactt cttgcctaaa agagacctac 780 ctccggatca agaagaatga atacagtatt cccaagcaca tcaaccccgt ggccgcctcc 840 ctcatccaga agatgcttca gacagatccc actgcccgcc caaccattaa cgagctgctt 900 aatgacgagt tctttacttc tggctatatc cctgcccgtc tccccatcac ctgcctgacc 960 attccaccaa ggttttcgat tgctcccagc agcctggacc ccagcaaccg gaagcccctc 1020 acagtcctca ataaaggctt ggagaacccc ctgcctgagc gtccccggga aaaagaagaa 1080 ccagtggttc gagagacagg tgaggtggtc gactgccacc tcagtgacat gctgcagcag 1140 ctgcacagtg tcaatgcctc caagccctcg gagcgtgggc tggtcaggca agaggaggct 1200 gaggatcctg cctgcatccc catcttctgg gtcagcaagt gggtggacta ttcggacaag 1260 tacggccttg ggtatcagct ctgtgataac agcgtggggg tgctcttcaa tgactcaaca 1320 cgcctcatcc tctacaatga tggtgacagc ctgcagtaca tagagcgtga cggcactgag 1380 tcctacctca ccgtgagttc ccatcccaac tccttgatga agaagatcac cctccttaaa 1440 tatttccgca attacatgag cgagcacttg ctgaaggcag gtgccaacat cacgccgcgc 1500 gaaggtgatg agctcgcccg gctgccctac ctacggacct ggttccgcac ccgcagcgcc 1560 atcatcctgc acctcagcaa cggcagcgtg cagatcaact tcttccagga tcacaccaag 1620 ctcatcttgt gcccactgat ggcagccgtg acctacatcg acgagaagcg ggacttccgc 1680 acataccgcc tgagtctcct ggaggagtac ggctgctgca aggagctggc cagccggctc 1740 cgctacgccc gcactatggt ggacaagctg ctgagctcac gctcggccag caaccgtctc 1800 aaggcctcct aa 1812

Claims (10)

A novel peptide analogue having the structure of Formula 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In the above formula (1), R is

/ RTI &gt; A composition for parenchyma comprising the novel peptide analogue of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof as an active ingredient. 3. The method of claim 2,
Wherein said novel peptide analogue, or a stereoisomer or pharmaceutically acceptable salt thereof, specifically binds to the poloxane domain of polo-like phosphorylase-1 (PLK1). 4. The method of claim 3,
Wherein said binding binds to the phosphorylated peptide binding site of the poloxane domain of polo-like phosphorylase-1. The method of claim 3,
Wherein the poloxane domain of polo-like phosphorylase-1 comprises the amino acid sequence of SEQ ID NO: 1. 5. The method of claim 4,
The phosphorylated peptide binding site comprises the 414th tryptophan, the 415th valine, the 416th aspartic acid, the 417th tyrosine, the 481st tyrosine and the 485th tyrosine in the amino acid sequence of the polo box domain of polo-like phosphorylase-1 comprising the amino acid sequence of SEQ ID NO: Tyrosine. &Lt; / RTI &gt; 3. The method of claim 2,
Wherein the novel peptide analog, or a stereoisomer or pharmaceutically acceptable salt thereof, is contained in the composition at a concentration of 1 to 500 [mu] M. 3. The method of claim 2,
Wherein the composition for parenteral administration inhibits oocyte maturation. Injecting the peptide analog of claim 1 into an immature oocyte of a mammal in vitro;
Injecting a contraceptive candidate into the immature oocyte;
Inducing the in vitro maturation of immature oocytes; And
A method for screening a contraceptive that specifically binds to the poloxane domain of polo-like phosphorylase-1 (PLK1), comprising measuring the degree of extracellular maturation. 10. The method of claim 9,
In the test tube, the peptide analog of claim 1 was injected into the immature oocyte of the mammal, and the contraceptive candidate substance was injected into the immature oocyte and the contraceptive candidate substance was not injected. Further comprising the step of determining the candidate substance as a new contraceptive agent when the degree of extracellular maturation is further reduced.

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