CN101974076B - Cyclic peptide for inhibiting cell proliferation and blood vessel hyperplasia induced by basic fibroblast growth factors - Google Patents
Cyclic peptide for inhibiting cell proliferation and blood vessel hyperplasia induced by basic fibroblast growth factors Download PDFInfo
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- CN101974076B CN101974076B CN2010105259546A CN201010525954A CN101974076B CN 101974076 B CN101974076 B CN 101974076B CN 2010105259546 A CN2010105259546 A CN 2010105259546A CN 201010525954 A CN201010525954 A CN 201010525954A CN 101974076 B CN101974076 B CN 101974076B
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Abstract
The invention discloses cyclic (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) peptide, which can be used for inhibiting the cell proliferation and blood vessel hyperplasia which are induced by basic fibroblast growth factors (bFGF), treating colon cancers and the like. The invention also discloses a medicinal composition containing the cyclic peptide, a preparation method thereof and the like.
Description
Technical field
The invention belongs to the peptide technical field; Particularly; The present invention relates to ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) peptide, it can be used for suppressing by the cell proliferation of bFGF inductive and blood vessel hyperplasia and the application that is used to treat aspects such as colorectal carcinoma.The pharmaceutical composition that comprises this cyclic peptide and preparation method etc. have been the invention still further relates to.
Background technology
Mammals fibroblast growth factor (Fibroblast growth factors; FGFs) family is made up of the polypeptide (FGF1-23) of 23 structurally associateds at least; Be one type to deriving from mesoderm and neuroectodermal polytype cell has the ESC of BA widely, acid FGF (aFGF) and basic FGF (bFGF) are considered to the prototype of whole FGFs protein family.Wherein, bFGF is one type of PGF that extensively is present in multiple tissue in the body, plays an important role at aspects such as tissue repair, wound healing, fetal development, Osteoblast Differentiation, blood vessel hyperplasias.BFGF distributes in vivo extensively and has multiple important biological function, and its spatial and temporal expression and expression level receive rigorous regulation and control.Research shows; Because bFGF has effects such as the various kinds of cell of promotion propagation and short blood vessel hyperplasia; The unusual rise that bFGF expresses can cause multiple pathology, as tumour etc. (referring to Rusnati M, Presta M. Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies. Curr Pharm Des; 2007,13:2025-2044; Cronauer MV; Schulz WA; Seifert HH; Et al. Fibroblast growth factors and their receptors in urological cancers:basic research and clinical implications. Eur Urol, 2003,43:309-319; And, Gross JL, Herblin WF; Dusak BA; Et al. Effects of modulation of basic fibroblast growth factor on tumor growth in vivo. J Natl Cancer Inst, 1993,85:121-131).
Through long-term and arduous research; And combining the fortune of some screenings, the inventor has obtained a kind of cyclic peptide, surprisingly; It can effectively suppress by the cell proliferation of bFGF inductive; Especially suppress propagation by bFGF inductive tumour cell, simultaneously also can anti-angiogenic hyperplasia, thus can be used for treating tumour such as colorectal carcinoma.This peptide can adopt prior art synthetic, and cost is low, but effective, applied widely.
Summary of the invention
The object of the present invention is to provide a kind of cyclic peptide and verivate thereof; Its beneficial effect is effectively to suppress by the cell proliferation of bFGF inductive; Especially suppress propagation by bFGF inductive tumour cell, simultaneously also can anti-angiogenic hyperplasia, thus can be used for treating tumour such as colorectal carcinoma; In addition, this peptide can adopt prior art synthetic, and cost is low, but effective, applied widely.
Particularly, aspect first, the invention provides ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) peptide or its pharmacy acceptable salt or ester.
Cyclic peptide among this paper can use " ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) " or " cyclo (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) " to exchange expression, all refers to the cyclic peptide that is shown below:
Normally link to each other between each amino-acid residue in the ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln), although the peptide that other keys link to each other is also contained within the scope of the invention through peptide bond.Preferably in first aspect of the present invention, ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) is that the carboxyl by the amino of Ala and Gln forms peptide bond and cyclisation forms.In embodiment of the present invention, any two adjacent amino acids all link to each other through peptide bond in the ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln).
The method for expressing that generally acknowledged in the field under the method for expressing of peptide used herein and amino acid, amino-acid residue and chemical group was.Wherein the abbreviation of amino acid or amino-acid residue can be with reference to definition in the table 1, and these abbreviations can refer to the amino acid of L-type, also can refer to the amino acid of D-type.In embodiment of the present invention, amino acid or amino-acid residue refer to the amino acid or the amino-acid residue of L-type.
Table 1 amino acid abbreviations table
For peptide of the present invention; Can carry out suitable modification, as, the amino-acid residue side-chain radical is modified to form pharmaceutically acceptable ester; The conjugate that ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) and polymer substance form, or the combination of these modifications etc.In this article, " pharmaceutically acceptable ester " refers to be suitable for contacting and not having with human or animal's tissue the ester of too much toxicity, stimulation or transformation reactions etc.Usually, can reduce proteolytic enzyme in the body after esterification is modified to the hydrolysis of peptide.The side-chain radical of cyclic peptide of the present invention modified to form pharmaceutically acceptable ester.Modification to the amino acid side chain group includes but not limited to the pendant hydroxyl group of Threonine and the esterification that carboxylic acid takes place.In embodiment of the present invention, preferably the amino acid side chain group of cyclic peptide is not modified.
Use methods known in the art, ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) can form conjugate with polymer substance, wherein, and the normally pharmaceutically acceptable water soluble polymerizer part of polymer substance.This conjugate generally can demonstrate the effect of the circulating half-life that prolongs cyclic peptide.Suitable water soluble polymerizer comprises polyoxyethylene glycol (PEG), mono methoxy-PEG, list-(C
L-10) alkoxyl group-PEG, aryloxy-PEG, gather-(N-V-Pyrol RC) PEG, the polymer of trimethoxy PEG, mono methoxy-PEG propionic aldehyde, PEG propionic aldehyde, two-succinimide carbonic acid PEG, propyleneglycoles homopolymer, polypropylene oxide/oxidation of ethylene composition copolymer, T 46155 polyol (like, glycerine), mono methoxy-PEG butyraldehyde, PEG butyraldehyde, mono methoxy-PEG acetaldehyde, PEG acetaldehyde, methoxyl group PEG-succinimide propionic acid, methoxyl group PEG-succinimide butyric acid, Z 150PH, DEXTRAN 500.000, Mierocrystalline cellulose or other carbohydrates.Suitable PEG can have about 600 to about 60,000 molecular weight, comprise like, 5,000 dalton, 12,000 dalton, 20,000 dalton, 30,000 dalton and 40,000 dalton, its can be straight chain or ramose.PEGization can carry out through PEGization reaction well known in the prior art (as referring to; The Critical Reviews in Therapeutic Drug Carrier Systems 9:249 (1992) of Delgado etc.; The Int J Hematol 68:1 (1998) of the Clin. Pharmacokinet. 27:290 (1994) of Duncan and Spreafico and Francis etc.).For example, the available reactive polyethylene glycol molecule of PEGization carries out by acylation reaction or by alkylated reaction.In optional method, conjugate is formed by condensation activatory PEG, and wherein terminal hydroxyl or the amino linkers that is activated of PEG substitutes (as referring to, Karasiewicz etc., US5382657A).Conjugate also can be the conjugate that ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) forms with other protein-crosslinking.The Fc part of the preferred human albumin of said other albumen, BAS or IgG molecule.For example, cyclic peptide of the present invention can be cross-linked to form peptide conjugate with bovine serum albumin.
In this article, " pharmacy acceptable salt " refers to be suitable for contacting and not having with human or animal's tissue the salt of too much toxicity, stimulation or transformation reactions etc.Pharmacy acceptable salt is well known in the art.This salt can also can prepare peptide and suitable organic or inorganic acid or alkali reaction separately in the final separation of polypeptide of the present invention and the process of preparing of purifying.Representative acid salt includes but not limited to acetate; Two hexanoates; Alginate; Citrate trianion; Aspartate; Benzoate; Benzene sulfonate; Hydrosulfate; Butyrates; Camphorate; Camsilate; Glycerophosphate; Hemisulphate; Enanthate; Hexanoate; Fumarate; Hydrochloride; Hydrobromate; Hydriodate; The 2-isethionate; Lactic acid salt; PHENRAMINE MALEATE; Mesylate; Nicotinate; The 2-naphthalenesulfonate; Oxalate; 3-phenylpropionic acid salt; Propionic salt; SUMATRIPTAN SUCCINATE; Tartrate; Phosphoric acid salt; Glutaminate; Supercarbonate; Tosilate and undecane hydrochlorate.The preferred acid that can be used to form pharmaceutically-acceptable salts is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, oxalic acid, toxilic acid, succsinic acid and Hydrocerol A.Positively charged ion in the pharmaceutically acceptable base addition salt includes but not limited to basic metal or alkaline earth metal ion such as lithium, sodium, potassium, calcium, magnesium and aluminium etc., and non-toxicity quaternary ammonium cation such as ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethyl amine, Trimethylamine, triethylamine, DIETHANOL AMINE, ethylamine, diethylamine, thanomin, diethylolamine, piperidines, piperazine etc.Preferred base addition salt comprises phosphoric acid salt, tris and acetate.These salt generally can increase the solvability of polypeptide, and formed salt does not change the activity of polypeptide basically.Polypeptide of the present invention can use separately, also can use with the pharmacy acceptable salt form.
In second aspect, the invention provides compsn, it comprises the described peptide of first aspect present invention or its pharmacy acceptable salt or ester, and pharmaceutically acceptable carrier." the pharmaceutically acceptable carrier " that uses among this paper refers to nontoxic solid-state, semi-solid state or liquid weighting agent, thinner, adjuvant, lapping or other pharmaceutical adjuncts.Known technology according to this area; Can pharmaceutical composition be processed various formulations according to the needs of therapeutic purpose, route of administration; Preferred said composition is a unit dosage form, like tablet, film, pill, capsule (comprise and continue to discharge or postpone releasing pattern), pulvis, granule, tincture, syrup and emulsion agent, disinfectant injection solution or suspension-s, aerosol or liquid spray, drops, injection, automated injection device or suppository.For example, with the oral administration that tablet or glue are assisted, above-mentioned active medicine component can be combined with a kind of oral acceptable inert support of nontoxic pharmacology, as ethanol, etc. ooze glucose solution, glycerine, saline water or other combination.Can also add auxiliary material in the compsn, like polypeptide protective materials such as human serum albumin, low molecular weight peptide, amino acid and metallic cation etc.In embodiment of the present invention, cyclic peptide of the present invention directly use damping fluid (as, PBS) be diluted to constituent.
Preferably in second aspect of the present invention, said compsn is a pharmaceutical composition, promptly reaches the compsn that medicinal purity, preparation etc. require.Pharmaceutical composition can carry out administration through the administering mode that one of ordinary skill in the art knew, and for example oral, rectum, hypogloeeis, lung, transdermal, ion penetrate, vagina and intranasal administration.The preferred gi tract external administration of pharmaceutical composition of the present invention is like subcutaneous, intramuscular or intravenous injection.Dosage changes according to the situation of action time of dosage form and expectation and treatment target to some extent, the required amount of actual therapeutic can by the doctor according to practical situation (as, patient's the state of an illness, body weight etc.) and confirm easily.For general adult, the dosage of pharmaceutical composition of the present invention in ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) peptide, can be that every kg becomes body weight for humans 1ng – 10g.For the drug administration by injection pattern, preferred dosage is every kg body weight 100ng-10mg, more preferably every kg 1mg-1mg, most preferably every kg 10mg-100mg.
In the third aspect, the invention provides the application in the compsn of preparation inhibition cell proliferation of the described peptide of first aspect present invention or its pharmacy acceptable salt or ester.Wherein said compsn can be a pharmaceutical composition, also can be the compsn that only is suitable for in-vitro application, preferably pharmaceutical composition.
Preferably in the third aspect of the invention, cell proliferation is by the Prostatropin inductive.The inventor finds after deliberation; Cyclic peptide of the present invention can suppress the propagation by Prostatropin inductive tumour cell specifically; Therefore also preferably in the third aspect of the invention, cell is a tumour cell, in embodiment of the present invention; Cell is a colon cancer cell, like Caco2 and LoVo cell.
In addition; In embodiment of the present invention; Therefore cyclic peptide of the present invention is unique inhibition proliferation activity composition, also preferably provides, the invention provides the described peptide of first aspect present invention or its pharmacy acceptable salt or ester as unique inhibition proliferation activity composition preparation suppress cell (as; Tumour cell is more preferably like colon cancer cell) propagation compsn in application.
In fourth aspect, the invention provides the application in anti-angiogenic outgrowth medicine of preparation or reagent of the described peptide of first aspect present invention or its pharmacy acceptable salt or ester.In this article, as do not have opposite indication, medicine can exchange with pharmaceutical composition and use; Reagent refers to the compsn that only is suitable for in-vitro application.
Preferably in fourth aspect of the present invention, blood vessel is the chick chorioallantoic membrane blood vessel.The inventor finds that after deliberation cyclic peptide of the present invention can suppress by Prostatropin inductive chick chorioallantoic membrane blood vessel hyperplasia specifically, and it uses as unique anti-angiogenic proliferative activity composition.Therefore also preferably provide, the described peptide of first aspect present invention or its pharmacy acceptable salt or ester are as the application of unique anti-angiogenic proliferative activity composition in outgrowth medicine of preparation anti-angiogenic (like, chick chorioallantoic membrane blood vessel) or reagent.
Aspect the 5th, the invention provides the application in the preparation anti-tumor drug of the described peptide of first aspect present invention or its pharmacy acceptable salt or ester.The inventor finds after deliberation; Cyclic peptide of the present invention not only can suppress the propagation of tumour cell itself separately, and can independent anti-angiogenic hyperplasia, thereby reduces the amount of blood supply of tumor tissues potentially; The effect of this two aspect that therefore superposes can be used to prevent and/or treat tumour.In preferably aspect the of the present invention the 5th, tumour is a colorectal carcinoma.
Aspect the 6th, the invention provides the method for preparing ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) peptide, it comprises, synthesizing linear peptide, cyclisation then.The method of sixth aspect present invention preferably includes, synthesizing linear peptide Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln, cyclisation then.Peptide through the synthetic known structure of chemical process all is conspicuous for one of ordinary skill in the art.Detailed scheme can be carried out with reference to the described method of following document; Can be as synthesizing polypeptide with reference to " Solid Phase Peptide Synthesis " (second edition of J.M. Steward and J.D. Young with solid phase method; Pierce Chemical Co., Rockford, Illinois (1984)) and " Hormonal Proteins and Peptides " (the 2nd volume of J. Meienhofer; Academic Press, New York (1973)) etc.; Can be with reference to " The Peptides " (the 1st rolls up Academic Press, New York (1965)) of E. Schroder and K. Lubke with the synthetic polypeptide of liquid phase method etc.Linear peptides has very sophisticated automatic synthetic technology at present, synthesizes as adopting commercially available automatic DNA synthesizer DNA.Cyclic peptide also can utilize special automatic DNA synthesizer DNA to synthesize, as utilizes the solid phase synthetic instrument of right-nitrophenyl ketoxime resin.But, the preferred first synthesizing linear peptide of the present invention, and then cyclisation.The method of existing linear peptides cyclisation includes but not limited to, direct method promptly adds condensation reagent, directly effective cyclic condensation in amino and carboxyl terminal all are the linear peptides dilute solution of unbound state; Active ester method is promptly processed the reactive behavior ester with nitro phenyl ester, HOSu NHS or pentafluorophenyl esters etc. with the carboxyl terminal of linear peptides, sloughs N end protection base then, makes it into ring; Azide method, the carboxyl terminal that is about to linear peptides is processed the acid azide reactive intermediate, Cheng Huan in the basic soln of dilution then, or the like.In a specific embodiments of the present invention, preferably through solid phase method elder generation synthesizing linear peptide, cyclisation then.
Preferably in sixth aspect present invention, the cyclic peptide after the cyclisation preferably is further purified, as carries out the HPLC purifying.Peptide of the present invention is the peptide of purifying preferably, promptly is purified to >=80% purity, and is preferred >=90% purity, and more preferably >=95% purity especially preferably reaches the state of pharmaceutical purity, and promptly purity is the purity more than or equal to 98%, and does not contain the source of infection and thermal source.Preferred peptide of the present invention does not contain those peptides or the protein of other polypeptide or protein, especially animal-origin in fact.
For the ease of understanding, below will carry out detailed description to the present invention through concrete embodiment.What need particularly point out is that these descriptions only are exemplary descriptions, do not constitute limitation of the scope of the invention.According to the argumentation of this specification sheets, many variations of the present invention, change have been obviously all concerning one of ordinary skill in the art.The open source literature quoted of the present invention is in order more clearly to describe the present invention in addition, and their full text content is all included this paper in and carried out reference, just looks like that repeated description is the same excessively in this article for their full text.
Embodiment
Synthesizing of embodiment 1 cyclic peptide
According to the method for known solid phase method synthesizing linear peptide and the method for cyclisation linear peptides, synthetic cyclic peptide of the present invention.In brief, use 413A type automatic peptide synthesizer (available from Perkin Elmer company) to come synthesizing linear peptide Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln, amino-acid residue wherein is the amino acid of L-type.The synthetic detailed process is following: at first, the reactive group on the protection amino acid monomer: amino acid whose α is amino to be protected with 9-fluorenylmethyloxycarbonyl (Fmoc); And following specific amino acids carried out side chain protected: the Side chain protective group to Ser and Thr is the tertiary butyl, is trityl (Trt) to the Side chain protective group of Gln.Then, with N, N-DIC/I-hydroxybenzotriazole makes the coupling successively of shielded amino acid as activating reagent, each 40 minutes of coupling.Under the situation that 15% dithioglycol/dimethyl sulphide/phenylmethylether (volume ratio is 1: 1: 1) exists, peptide and trifluoroacetic acid (85%) be room temperature reaction 120 minutes, thereby cut down from the polymer upholder.Then use the anhydrous diethyl ether precipitation of peptides, repeatedly wash with anhydrous diethyl ether then, fully remove mercaptan.Deposition in water/trimethyl carbinol (1: 1), lyophilize obtains linear peptides.
With the synthetic linear peptides with the mol ratio of 1:1.5 and p-nitrophenol mixed dissolution in ETHYLE ACETATE; Add condensing agent 1; 3-NSC 57182 (DCC); Obtain the nitrated peptide of linear peptides C-terminal, add the protection base of trifluoroacetic acid (85%) deaminize end then, remove Side chain protective group simultaneously.After boiling off solvent, solid product is dissolved in 0.1M NaHCO
3With 0.1M Na
2CO
3Dioxane solution in, in room temperature reaction 3 hours.Then use the anhydrous diethyl ether precipitation of peptides, repeatedly wash with anhydrous diethyl ether then, deposition in water/trimethyl carbinol (1: 1), lyophilize obtains the cyclic peptide bullion.With the cyclic peptide bullion in 30 minutes with the reversed-phase HPLC purifying, with 37-42% second fine/the 0.9%TFA gradient carries out.Concentrate then, freeze-drying, obtain ring (Ala-Thr-Leu-Gly-Gly-Gly-Ser-Pro-Leu-Leu-Gln) peptide of purifying thus, detect its purity >=98% through HPLC.
Embodiment 2 cyclic peptide are to the influence of tumour cell survival rate
Interstital stem cell HUMSC strain (as the strain of non-tumour control cells) and colon cancer cell line Caco2 and LoVo (all can available from ATCC) be placed the hole of 96 orifice plates, 5000 cells in every hole respectively.Wherein, HUMSC, Caco2 and LoVo cell are cultivated in the DMEM substratum that has added 10% foetal calf serum after 24 hours respectively, discard substratum, add in the DMEM substratum of 0.4% foetal calf serum to continue to cultivate 24 hours.Then, medium volume adds cyclic peptide, 20ng/ml bFGF and the cyclic peptide of different dilution embodiment 1 preparation and the mixture of 20ng/ml bFGF that different dilution embodiment 1 prepare in each hole respectively, continues to cultivate 48 hours.According to mtt assay, measure the effect of cell proliferation, promptly use the quantity of Thiazolyl blue color developing detection viable cell.The result finds, in the time of independent adding 20ng/ml bFGF, these two kinds of colon cancer cells and control cells strain all have remarkable propagation; In the time of the cyclic peptide of different dilution embodiment 1 preparations of independent adding, the quantity of these two kinds of colon cancer cells and control cells strain all not have significant the change, does not promptly significantly increase, not significantly minimizing yet; In the time of the mixture of cyclic peptide that adds different dilution embodiment 1 preparations and 20ng/ml bFGF; These two kinds of colon cancer cells influenced by 20ng/ml bFGF and the amplitude of breeding obviously reduces; The amount that reduces is the cyclic peptide dose-dependently; Through calculating, cyclic peptide is 3.8 μ M to the 503nhibiting concentration (IC50) of 20ng/ml bFGF inductive Caco2 cell proliferation, and is 0.77 μ M to the 503nhibiting concentration (IC50) of 20ng/ml bFGF inductive LoVo cell proliferation.
Embodiment 3 cyclic peptide are to the influence of blood vessel hyperplasia
According to Li, and X etc. (Cancer Letter, 2007,256:29-32) reported method is measured cyclic peptide in vivo to the influence of chick chorioallantoic membrane blood vessel hyperplasia.That is, 56 5 days big or small chicken embryos are divided into seven groups at random,, on the eggshell of chorioallantoic membrane, are rasped to a trilateral slight crack, bore an aperture at the air chamber top simultaneously, remove shell breaking and cause " ovum window ", do not injure shell membrane through according to looking; Ovum is kept flat,, make and form artificial air chamber between shell membrane and the chorioallantoic membrane through causing the air chamber negative pressure; PBS (as blank), bFGF (30ng/ml) and bFGF (30ng/ml) and 5 extent of dilution (0.05 μ M with equal-volume (20 μ l); 0.2 μ M; 0.8 μ M, 3.2 μ M, 12.8 μ M) the blend sample of cyclic peptide of embodiment 1 preparation place on the chorioallantoic membrane respectively; Cover the ovum window with zellglas, be coated with on every side with melting wax sealing, closed air chamber aperture simultaneously; With the accumbency of chicken embryo, hatch the chicken embryo after 72 hours, the observation vessel density in 37 ℃.The result finds that with respect to the PBS contrast, bFGF can significantly promote blood vessel hyperplasia; Yet; If added the cyclic peptide of different dilution embodiment 1 preparations among the bFGF simultaneously; Then when cyclic peptide concentration less than 0.8 μ M the time, cyclic peptide is the effect that dose-dependently ground suppresses the short blood vessel hyperplasia of bFGF, when concentration reaches 0.8 μ M and above the time; The effect that has suppressed the short blood vessel hyperplasia of bFGF fully, promptly the level of blood vessel hyperplasia and PBS control group is suitable.
Claims (1)
1. in the medicine of the anti-chick chorioallantoic membrane blood vessel hyperplasia of preparation or the application in the reagent, said cyclic peptide forms peptide bond and cyclisation by the amino of Ala and the carboxyl of Gln to the cyclic peptide that is shown below as unique anti-angiogenic proliferative activity composition
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Non-Patent Citations (2)
| Title |
|---|
| Cong Wang，et al.Mechanism of antitumor effect of a novel bFGF binding peptide on human colon cancer cells.《Cancer Science》.2010,第101卷(第5期),1212-1218. * |
| Xiaoping Wu,et al.Isolation of a novel basic FGF-binding peptide with potent antiangiogenetic activity.《J. Cell. Mol. Med.》.2010,第14卷351-356. * |
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