CN103288926B - Tubulin polymerization agent polypeptide and application thereof - Google Patents
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- CN103288926B CN103288926B CN201310208866.7A CN201310208866A CN103288926B CN 103288926 B CN103288926 B CN 103288926B CN 201310208866 A CN201310208866 A CN 201310208866A CN 103288926 B CN103288926 B CN 103288926B
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to the field of medicaments, and in particular relates to a polypeptide which can promote the polymerization of tubulin and treat acute lymphocytic leukemia. The sequence of the polypeptide is EVVPFQEVWGRSYCRA and is a new sequence; the polymerization of the tubulin can be promoted by 1 micromolar level of the polypeptide in vitro, and the survival rate of tumor-bearing mice can be increased in vivo experiments; and therefore, the polypeptide has a potential new medicament development value.
Description
Technical field
The present invention relates to tubulin polymerization agent polypeptide 8 and application thereof, be specifically related to have the polypeptide that promotes tubulin polymerization, treatment acute lymphoblastic leukemia.
Background technology
Acute lymphoblastic leukemia (ALL) is carrying out property of one malignant disease, it is characterized by a large amount of lymphoblastic neocytes that is similar to.These cells can be found in blood, marrow, lymphoglandula, spleen and other organ.Acute lymphoblastic leukemia accounts for 80% of acute leukemia, and sickness rate peak is between 3 years old to 7 years old.ALL also can betide grownup, accounts for all grownups leukemic 20%.Along with the going deep into of medical research, understanding and treatment to acute lymphoblastic leukemia have made great progress in recent years.Wherein, tubulin is being played the part of key player in acute lymphoblastic leukemia.
Microtubule is the chief component of cytoskeleton, by
α-tubulin and
β-tubulin heterodimer forms, and has the feature of hollow tubular structure.In addition, also has one
γtubulin, it is not the moiety of microtubule, but participates in the assembling of microtubule.Microtubule has the dynamics of Aggregation and disaggregation, plays an important role maintaining in the processes such as cellular form, cell fission, signal transduction and material conveying.Microtubule becomes spindle body in prophase of cell division polymerization, moves in two daughter cells to the two poles of the earth and spindle body draws karyomit(e) in mitotic division, completes cell proliferation.The assembling process of microtubule be α-and 'beta '-tubulin opposite sex dimer between noncovalent interaction closely, this process is driven by GTP hydrolysis.Opposite sex dimer constantly, in the positive pole growth of microtubule, shrinks at negative pole, and maintains dynamic stability.In the time that the dynamic stability of microtubule is destroyed, the mitotic division process of cell is just likely prevented from, thereby causes necrocytosis.Because microtubule has extremely important effect in cell fission, now become one of important target spot of antitumor drug research.
Antitubulin has two kinds of sorting techniques.A kind of is to be divided into two types according to the difference of mechanism of action: the tubulin depolymerizing agent that 1. suppresses tubulin polymerization; 2. promote the tubulin polymerization agent of tubulin polymerization.
Promote the tubulin polymerization agent of tubulin polymerization to have the compounds such as taxol, be used for oncotherapy.This compounds is characterized in the tubulin depolymerizing agent in the vinealeucoblastine(VLB) site that acts on microtubule.Research shows, after taxol and cells contacting, can rupture by induce dna, causes apoptosis.In addition, it can also inducing cell in tumour necrosis factor
α(TNF-
α) expression of gene, improve protein, comprise the phosphorylation level of MAP kinases and the kinase whose tyrosine residues of Raf-1.In December, 1992, U.S. FDA has been ratified the treatment of taxol for mammary cancer and ovarian cancer.Its application clinically that taxol has had 3 important effects limit: (1) taxol content in several Chinese yew genus plants is very low, is restricted source; (2) water-soluble relatively low, receptivity is poor; (3) the cancer cells meeting overexpression P-glycoprotein of crossing by taxol treatment, has multidirectional resistance.
Therefore, need to develop good water solubility, the little tubulin polymerization agent of side effect is used for the treatment of acute lymphoblastic leukemia.Tubulin polymerization agent comprises macromole and small molecules.The preparation of macromole polymerizing agent and use have limited their development, and for example recombinant human tubulin promotes the Half-life in vivo of the factor to only have 4 minutes.A lot of successfully small molecules polymerizing agents, can in nmole level, promote the vigor of tubulin, but small molecules polymerizing agent lack specificity, if long-term use lacks specific tubulin polymerization agent and can produce larger side effect in chronic disease.Thereby, from the application point of tubulin polymerization agent, be correct selection using acute lymphoblastic leukemia as research object.At Acute response stage, body can tolerate inhibition short-term, tubulin wide spectrum polymerizing agent Normal Physiological Function, makes the physiological structure of critical tissue's organ avoid destroying simultaneously, has increased chances of survival.
Tubulin polymerization agent polypeptide 8 in this patent has proved in acute lymphoblastic leukemia effective, has the prospect of developing in other tumor models.
Summary of the invention
goal of the invention
The invention provides brand-new sequence, this sequence tubulin polymerization agent, has good curative effect to acute lymphoblastic leukemia.
technical scheme
tubulin polymerization agent polypeptide 8, is characterized in that its sequence is EVVPFQEVWGRSYCRA.
The application of tubulin polymerization agent polypeptide 8 in preparation treatment acute lymphoblastic leukemia medicine.
beneficial effect
Utilize solid-phase synthesis chemosynthesis tubulin polymerization agent polypeptide 8, this polypeptide has brand-new sequence, and this polypeptide can external promotion tubulin, treatment acute lymphoblastic leukemia.In endotoxin shock model experiment, successfully increase the survival rate of mouse.The tubulin polymerization agent polypeptide 8 that we find can promote tubulin polymerization vigor simultaneously, and in test, improves tumor-bearing mice survival rate in vivo, has potential new drug development and is worth.
Embodiment
polypeptide of the present invention is synthetic by the raw work in Shanghai.
Embodiment 1
The effect of tubulin polymerization agent polypeptide 8 to external tubulin polymerization and depolymerization.
Get fresh cow brain tissue, peel off meninx and large blood vessel, shred, with cold MES damping fluid washing 1-2 time, organize the ratio of 0.5-1ml to add MES damping fluid with every Borneo camphor, at 4 DEG C, use electric homogenizer homogenate; 4 DEG C, the centrifugal 1h of 105000g, gets supernatant, adds isopyknic microtubule polymerization damping fluid, 37 DEG C of water bath heat preservation 30min.26 DEG C, the centrifugal 1h of 105000g, gets precipitation, adds the cold MES damping fluid of approximately 1/10 homogenate volume, stirs gently or precipitation is pulverized with homogenizer; Suspension is put to ice bath 30min, precipitation is dissolved completely.With Lowry ' s method mensuration protein content (SDS polyamide gels electrophoretic method).Tubulin is diluted to 4-5mg/ml with MES damping fluid, puts in liquid nitrogen and preserves.Get freezing tubulin solution, rush its wall by normal-temperature water fast, make it to melt, put into ice bath, be diluted to desired concn (2-3mg/ml) with MES damping fluid, add ATP to 1mmol/l.Set up as " 0 " point at spectrophotometer 350nm taking the tubulin solution taking out from ice bath at once.Then cuvette is measured at 37 DEG C of temperature to the OD value of tubulin solution, 20-30min, records temperature-light absorption value curve (T-OD curve), in triplicate continuously.
Inhibiting rate calculates: inhibiting rate (%)=(control tube " OD " value-chemical feed pipe " OD " value)/control tube " OD "
Experimental group is established five dosage: 0.75 μ M, 1.5 μ M, 3 μ M, 12 μ M, 24 μ M, and positive controls dose of paclitaxel 3 μ M, blank group adds isopyknic solvent DMSO; Press aforesaid operations and measure light absorption value.As a result, increase with tubulin polymerization agent polypeptide 8 concentration, polymerization retardation rate raises gradually, illustrates that the tubulin of polymerizing power constantly strengthens with the increase of drug level.
Embodiment 2
Growth and the survival IC50 of tubulin polymerization agent polypeptide 8 to cultured tumor cells in vitro.
Adopt MTT colorimetry.By the U937 cell of logarithmic growth, add in 96 well culture plates with 1.0 × 105, cultivate 24h, experimental port, positive drug control wells add respectively Experimental agents tubulin polymerization agent polypeptide 8 and the positive control medicine taxol of different concns; Blank group adds the solvent of same volume.Five multiple holes are established in every hole, cultivate 48h, respectively 0h, 2h, 8h, 14h, 20h, 24h, 36h,, the every hole of 48h adds MTT, after effect 4h, add DMSO, hatch 30min, measure absorbance A value at microplate reader 620nm place, by formula growth of tumour cell inhibiting rate=(1-experimental group light absorption value/control group light absorption value) × 100%.The IC50 that calculates Experimental agents is 4.66 μ M.
Embodiment 3
With vigor in the body of tumor model detection tubulin polymerization agent polypeptide 8.
Set up U937 tumor model, positive control medicine taxol; Blank group adds the solvent of same volume, and experimental group is established 3 dosage: 0.75,1.5 μ M, 3 μ M mg/Kg.After 21 days, observe mouse survival quantity, calculate survival rate.Result demonstration, tubulin polymerization agent polypeptide 8 can be protected small white mouse effectively, improves the survival rate of tumor-bearing mice, and survival rate reaches 81.4%.
SEQUENCE LISTING
Pu Luoda bio tech ltd, <110> Suzhou
<120> tubulin polymerization agent polypeptide and application thereof
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 16
<212> PRT
<213> artificial sequence
<400> 1
Glu Val Val Pro Phe Gln Glu Val Trp Gly Arg Ser Tyr Cys Arg Ala
1 5 10 15
Claims (2)
1. tubulin polymerization agent polypeptide 8, is characterized in that its sequence is EVVPFQEVWGRSYCRA.
2.
a kind of claimed in claim 1the application of tubulin polymerization agent polypeptide 8 in preparation treatment acute lymphoblastic leukemia medicine.
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| CN201310208866.7A CN103288926B (en) | 2013-05-30 | 2013-05-30 | Tubulin polymerization agent polypeptide and application thereof |
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