CN101225106B - Short peptide suppressing growth of cancer cell and uses thereof - Google Patents
Short peptide suppressing growth of cancer cell and uses thereof Download PDFInfo
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Abstract
The invention provides a short peptide capable of inhibiting the growth of cancer cell, which is characterized in that the identity and similarity of the amino acid main sequence of the short peptide fragments, the analogues, the derivatives and the variants of the short peptide to the amino acid main sequence of the short peptide are greater than or equal to 70% and 90% respectively; the short peptides, the nucleotides, the short peptide fragments, the short peptide analogues, the short peptide derivatives and the short peptide variants can be used in preparing drugs for curing leukaemia caused by various lesion cell proliferation of non-solid tumor human myeliod line, curing various cancers caused by human solid tumor cancer cell proliferation, inhibiting hypertension, and diagnosing and detecting the occurrence and the malignancy of cancers; the short peptides and the nucleotides also can be used in preparing drugs which are used as protease inhibitor, accelerator, affinity reagent, or detection reagent. The short peptide capable of inhibiting the growth of cancer cell has an advantage of overcoming the defect of serious harmful effect on the normal cell of human body when the existing cancer drugs are used for inhibiting or killing the cancer cell.
Description
Technical field
The invention belongs to the biotechnology field of medicaments, the present invention has more specifically related to a kind of small peptide and application thereof of anticancer growth.
Background technology
In the process of cancer generation and treatment, chemotherapy one is directly subordinate to main part.The chemotherapeutics of existing clinical use, as endoxan, cis-platinum, cytosine arabinoside, adriamycin and vincristine etc., they mainly are the cycles that is used for destroying cell, RNA, DNA and protein all are the target targets of this type of medicine.In recent years, As
2O
3On for leukemic treatment, obtained very big progress, but, this medicine and other chemotherapeutics, itself all has the toxicity of oneself, no matter be that a kind of chemotherapeutics uses separately or the combination of several chemotherapeutics is used on the clinical treatment, it is having obvious curative effects to cancer, when killing and wounding kill cancer cell, also can damage patient's normal cell.The side effect of chemotherapeutics is the most general is exactly that marrow to patient produces extremely and suppresses, and causes patient's very big misery, even causes death.Up till now, except early finding the cancer state of an illness and carrying out the ocal resection enclosed mass, still there is not specific medicament to remove treatment [Cancer Biology cancer biology for tumour that has spread and leukemia, R.J.B gold work, Liu Yixun master translates, Science Press, 2002], the existing medicine that is used for cancer therapy clinically mostly is a compound, and the application of small peptide aspect cancer still do not have bibliographical information.
Summary of the invention
The present invention seeks at the problems referred to above, a kind of small peptide and application thereof of anticancer growth are provided.
The small peptide of a kind of anticancer growth of the present invention is characterized in that: amino acid chief series＜1 of forming small peptide〉and Nucleotide chief series＜2 of the small peptide of encoding as follows:
＜1〉J-Leu-B-Ser-O-Ala-Lys wherein, J represented amino acid Lys, Thr or Ile; B represented amino acid Pro or Leu; O represented amino acid Ser or Ala;
＜2〉AHA CTG CMT TCA NCT GCC AAA wherein, H represents Nucleotide T, A or C; M represents Nucleotide T or C; N represents Nucleotide T or A.
The small peptide fragment of anticancer growth of the present invention, its amino acid chief series has the homogeny with this small peptide amino acid chief series 〉=70%, 〉=90% similarity, fragment have same bioactive small peptide for what described 7 amino acid whose sequences are intercepted into 3 or 4 or 5 or 6 amino acid compositions from the optional position with described small peptide.
The small peptide analogue of anticancer of the present invention growth has the biological activity identical with described small peptide, and described analogue is meant at the peptide sequence or the protein that merge or form with the other polypeptide of the aminoacid sequence fusion of described small peptide or protein biologically active with described small peptide and another kind of compound.
The small peptide derivative of anticancer growth of the present invention, its aminoacid sequence has the homogeny with small peptide amino acid chief series 〉=70%, 〉=90% similarity, this derivative are meant that amino acid whose one or several amino acid whose certain groups in the described amino acid whose sequence are replaced the back with other group has same bioactive small peptide with described small peptide.
The small peptide variant of anticancer growth of the present invention, its aminoacid sequence has the homogeny with small peptide amino acid chief series 〉=70%, 〉=90% similarity, this variant is meant a kind of nucleotide sequence that has the aminoacid sequence of one or several amino acid or Nucleotide change or encode it, described change is included in aminoacid sequence or the nucleotide sequence, at the arbitrary topagnosis of sequence intermediary, insertion or replacement amino acid or Nucleotide, or at sequence two ends interpolation amino acid or Nucleotide.
The application of the grade malignancy medicine that are used to small peptide of the present invention, Nucleotide, small peptide fragment, small peptide analogue, small peptide derivative and small peptide variant the prepare leukemia that has all kinds of sick cell hyperplasia of the non-noumenal tumour people medullary system of treatment and cause, all kinds of cancers for the treatment of people's noumenal tumour cancer cell multiplication, the generation that suppresses hypertension, diagnoses and detect cancer and cancer take place.
Small peptide of the present invention or Nucleotide are used to prepare and have as the medicine of proteinase inhibitor or promotor or affinity reagent or the application of detection reagent.
Remarkable advantage of the present invention is: small peptide of the present invention comes from the method for using information biology the albumen of international Protein Data Bank is carried out sequence alignment, a kind of novel biologically active peptides that screens with active function, when using small peptide inhibition of the present invention or killing and wounding cancer cells normal cell is not had remarkable injury effect, solved existing cancer drug also has grievous injury to the human normal cell in inhibition or kill cancer cell defective.
Description of drawings
Fig. 1 is the test photo that small peptide of the present invention suppresses liver cancer cell growth.Wherein, (a) experimental group (Test) is the microphotograph with remarkable inhibition effect; (b) control group (Control) is not for adding the negative control test microphotograph of this small peptide.
Fig. 2 is the test-results that flow cytometer check analysis small peptide of the present invention suppresses the leukemia cell.(a) experimental group (Test), (b) control group (Control).
Fig. 3 is the Ultrastructural test-results of utilization transmission electron microscope check analysis cervical cancer cell.
Fig. 4 is that small peptide suppresses hypertensive test-results.
Embodiment
The preparation method of small peptide adopts the method for chemosynthesis, and very sophisticated solid-phase peptide synthetic method promptly well known in the art both can adopt the Boc method also can adopt the Fmoc method.Specific practice is coupled to the inertia solid phase carrier one by one with protected amino acid exactly and gets on, and utilizes strong acid that peptide chain cracking from the carrier is got off then, removes side chain protected simultaneously.
The amino acid main sequence of small peptide is classified amino acid position fixed chief series as, its choice of location is at interval arranged corresponding amino acid, for example, amino acid in the J position has 3 kinds of Lys, Thr or Ile, this 3 seed amino acid can be placed in singlely＜1 on the position of J, no matter select wherein any, this small peptide still has its original biological activity, promptly suppresses malignant cell and increases, and similarly the amino acid of the position of B and O representative also has characteristic like this.
Nucleotide adopts the artificial synthesis preparation; The Nucleotide of coding small peptide comprises a kind of in the following group:
(a) coding has the small peptide of described aminoacid sequence or the Nucleotide of its fragment, analogue, derivative or its variant;
(b) with (a) described Nucleotide complementary Nucleotide;
(c) with (a) or Nucleotide (b) have 〉=Nucleotide of 75% homogeny;
This Nucleotide substantially by coding have＜Nucleotide of 1〉aminoacid sequence small peptide forms, nucleotide sequence of the present invention comprises＜2 in nucleotide sequence, its form is the DNA that dna form comprises cDNA or synthetic.DNA can be strand also can be double-stranded.The coding region sequence of coding small peptide can be with＜2〉in Nucleotide identical, also can be different, be called varient, wherein varient be meant and has coding＜1〉in the coding of aminoacid sequence, but can be with＜2 in Nucleotide different.Varient can be that one or several Nucleotide replaces, inserts, the nucleotide sequence of disappearance, but can not change coding＜1〉active function of the small peptide of middle aminoacid sequence.
" variant " of this small peptide or Nucleotide is meant a kind of nucleotide sequence that has the aminoacid sequence of one or several amino acid or Nucleotide change or encode it.Change can comprise disappearance, insertion, interpolation or the replacement of amino acid in aminoacid sequence or the nucleotide sequence or Nucleotide.Variant can have " conservative property " and change, and wherein the amino acid of Ti Huaning has structure or the chemical property similar with original acid, also can have " non-conservation " to change, and wherein the amino acid of Ti Huaning does not have structure or the chemical property similar with original acid." disappearance " is meant the disappearance of in aminoacid sequence or nucleotide sequence one or several amino acid or Nucleotide; " insertion " is meant in the middle optional position of aminoacid sequence or nucleotide sequence and inserts one or several amino acid; N end or C end that " interpolation " is meant at aminoacid sequence or nucleotide sequence add one or several amino acid; " replacement " is meant with different amino acid or Nucleotide and replaces one or several amino acid or Nucleotide.
This small peptide, Nucleotide, small peptide fragment, small peptide analogue, small peptide derivative and small peptide variant are used to prepare have and suppress and the purposes for the treatment of the medicine that includes but not limited to following disease:
1. non-noumenal tumour marrow series leukemia: acute nonlymphocytic leukemia (M1: undifferentiated myeloblastic leukemia; M2: the myeloblastic leukemia of part differentiation; M3: acute promyelocytic leukemia; M4: acute grain, monocytic leukemia; M5: acute monocytic leukemia; M6: acute erythremic myelosis or erythroleukemia; M7: acute megakaryocytic leukemia), acute lymphoblastic leukemia, chronic myelocytic leukemia, chronic grain-unicellular leukemia, the leukemia of the cell malignant proliferation type of chronic monocytic leukemia and other specific types.
2. noumenal tumour cancer: the Cancerous disease of liver cancer, cervical cancer, mammary cancer, cancer of the stomach, intestinal cancer disease and other malignant cell propagation type.
3. high blood pressure disease: essential hypertension and excitability hypertension.
When the amino acid chief series that calculates small peptide fragment, small peptide derivative and small peptide variant had with the homogeny of small peptide amino acid chief series and similarity, " homogeny percentage " was meant the identical percentage of sequence during two or more amino acid or nucleotide sequence are relatively.According to Cluster method (Higging D.G.﹠amp; Sharp P.M., Gene 1988,73:234-237) by checking distance between all pairings with each group series arrangement cluster, then with each bunch with in pairs or become set of dispense.Homogeny percentage between two aminoacid sequences such as sequence A and the sequence B calculates by following formula:
After " similarity " was meant that the same acid sequence position is determined in determining two aminoacid sequence comparisons, the amino acid whose conservative property of the correspondence of arranging between same amino acid replaced degree.Amino acid score PAM250 scoring matrix (Dayhoff, M.Schwartz, R.M.and Orcutt, B.C.Atlas of Protein Structure1978, the 345-352 known according to the biology information technology field; DeLisi, C.and Kanehisa, M.Mathematical Biosciences 1984.69:77-85; Schwartz, R.M.and Dayhoff, M.O.Atlas of Protein Structure, 1979.353-358), and when corresponding different aminoacids relatively during score 〉=0, these two amino acid similarities; When different aminoacids score＜0, two amino acid dissmilarities.Similarity percentage between two aminoacid sequences such as sequence C and the sequence D calculates by following formula:
Wherein, in the sequence C at interval residue number and the sequence D at interval residue number do not comprise similar amino acid whose number.
Below in conjunction with embodiment, further set forth the present invention.These implementation examples only are used to the present invention is described and are not used in and limit the scope of the invention.Following all enumerate all related synthetic small peptides of embodiment and all have the pharmic function that the present invention relates to and be not limited to cited function.
Embodiment 1
Suppress the test (the synthetic small peptide that the present invention relates to: Lys-Leu-Pro-Ser-Ser-Ala-Lys or Lys-Leu-Pro-Ser-Ala-Ala-Lys) of liver cancer cell
The cultivation of Bel7402 Bel-7402 cell is to cultivate with RPMI 1640 substratum that contain 10% new-born calf serum, with 5 * lO
5The cell density kind in/hole is implanted 96 porocyte plates, after 24 hours, the small peptide that the present invention relates to is joined in the Tissue Culture Plate according to different concentration, with isopyknic PBS is control group, with the cell counting count board counting, administration group and control group relatively obtain the inhibiting rate of liver cancer cell after 24 hours.As scheme shown in the l, the photo that small peptide that the present invention relates to and the human liver cancer cell acting in conjunction microscopically after 24 hours is taken, cell among the administration group Test can be observed significant inhibition effect significantly, cancer cells becomes " circle " shape by " shuttle " deformation of attached cell under the effect of small peptide medicine, and the cell shape among the control group Control still is " shuttle " shape.
Embodiment 2
Suppress acute myeloblastic leukemia (M
2) (the synthetic small peptide derivative that the present invention relates to is at the Serine acids base group modification that phosphorates: Thr-Leu-Pro-Serp-Ala-Ala-Lys)
The cultivation of people's acute myeloblastic leukemia clone HL60 cell is to cultivate with RPMI 1640 substratum that contain 10% new-born calf serum, with 10
6The cell density kind in/hole joins the small peptide that the present invention relates in the Tissue Culture Plate according to different concentration after implanting 24 porocyte plates at once, is control group with isopyknic PBS, existing clinical medicine As
2O
3As positive control, after 24 hours, detect (FACS) through flow cytometer, experimental result as shown in Figure 2, wherein upper limit on the right 59.32% is represented the quantity of dead cell, and 38.91% represents the quantity of viable apoptotic cell, and the repressed total effective rate of cell surpasses 98%.
Embodiment 3
Cervical cancer cell apoptosis check (the synthetic small peptide fragment that the present invention relates to, 4 or 5 amino acid: Thr-Leu-Pro-Ser of intercepting or Leu-Pro-Ser-Ser-Ala in sequence)
Human cervical carcinoma cell is that the cultivation of HeLa cell is to cultivate with RPMI 1640 substratum that contain 10% new-born calf serum, with 10
6The cell density kind in/hole joins the small peptide that the present invention relates in the Tissue Culture Plate according to different concentration after implanting 24 porocyte plates at once, is control group with isopyknic PBS, existing clinical medicine As
2O
3As positive control, after 24 hours, removing supernatant behind the cell centrifugation, after fixed cell particle before 3% glutaraldehyde-1.5% Paraformaldehyde 96 1 day (4 ℃), fixing 1.5h behind 1% osmic acid-1.5% yellow prussiate of potash, PBS rinsing; 70% alcoholization acetic acid uranium dye liquor piece dyes, alcohol-acetone gradient dehydration, Resins, epoxy 618 embedding medium embeddings.Ultrathin section(ing) 80nm, acetic acid uranium, the lead citrate 5min that respectively dyes; Observe under the Hu-12A of Hitachi type or Philip EM 208 type transmission electron microscopes, experimental result is observed apoptotic whole process as shown in Figure 3, and wherein, a is a viable apoptotic cell; B and c assemble caked apoptotic cell for the chromatin pyknosis; E transfers to die late period, produces to have the apoptotic body that nucleus is fragmented into polylith.
Embodiment 4
Suppress hypertension (the synthetic small peptide that the present invention relates to: Ile-Leu-Leu-Ser-Ser-Ala-Lys or Lys-Leu-Leu-Ser-Ser-Ala-Lys)
(angiotensin converting enzyme ACE), just can suppress the hypertension effect to suppress Zinc metallopeptidase Zace1.ACE suppresses active measuring method, according to Cushman method (Cushman D W, Cheung H S.Spectrophotometerassay and properties of the angiotensin-converting enzyme of rabbit lung.BiochemPharmacol, 1971,20:1637-1648.) and improved CZE method (Zhang R Z, Xu X H, Chen T B, et al.An assay for angiotensin-converting enzyme using capillary zone electrophoresis.Analytical Biochemistry, 2000,280:286-290.) measure.ACE acts on the tripeptides, can make it reaction and generate dipeptides and urobenzoic acid, and the urobenzoic acid that generates by assaying reaction is used for identifying the ACE activity.Amount that ACE suppresses the active urobenzoic acid that then generates from the mixed reaction solution that adds testing sample and relatively the drawing of urobenzoic acid amount that with separatory elution buffer is the mixed reaction solution generation of contrast.The amount of the urobenzoic acid that generates by the contrast and the reaction of testing sample is calculated the peak area of urobenzoic acid with integration, utilizes following formula to calculate inhibiting rate (Rm): Rm=[(A-B)/and A] * 100
Wherein: A is the peak height or the peak area of the urobenzoic acid of barren mixed reaction solution; B is the peak height or the peak area of the urobenzoic acid of the mixed reaction solution of adding testing sample.
It is 0.216mg/mL (dissolving with PBS) (as Fig. 4) that the small peptide that the present invention relates to is prepared into concentration, get 5 μ L, 10 μ L, 20 μ L, 50 μ L, 100 μ L, organize in contrast with isopyknic PBS and to carry out the HPLC stratographic analysis, process of the test: the damping fluid that is used for lytic enzyme and substrate is the boric acid of 0.1M and the NaCl of 0.5M, the damping fluid that is used for the HPLC wash-out is the boric acid of 0.05M and the NaCl of 0.3M, the concentration of substrate tripeptides is 25mM, gets ACE enzyme 5 μ L and dilutes 100 μ L, gets this diluent 5 μ L and isopyknic sample mix, behind 37 ℃ of insulation 10min, add 25 μ L substrate tripeptides, 37 ℃ are incubated 30min, add the HCl termination reaction of 42.5 μ L 1N, the centrifugal sample 10 μ L that go up.Chromatographic condition is flow 0.25mL/min, wavelength 228nm.
Embodiment 5
Suppressing the test of lung carcinoma cell (synthesizes the small peptide variant that the present invention relates to, promptly increases a Gla amino acid at the sequence of N end: Gla-Ile-Leu-Pro-Ser-Ala-Ala-Lys)
The cultivation of human lung cancer cell line A549 cell is to cultivate with RPMI 1640 substratum that contain 10% new-born calf serum, with 5 * 10
5The cell density kind in/hole is implanted 96 porocyte plates, after 24 hours, the small peptide that the present invention relates to is joined in the Tissue Culture Plate according to different concentration, with isopyknic PBS is control group, 24, count with cell counting count board respectively after 48 hours, administration group and control group compare, and the inhibiting rate that obtains lung carcinoma cell reaches 76%.
Embodiment 6
Test (the synthetic small peptide that the present invention relates to: Ile-Leu-Pro-Ser-Ala-Ala-Lys) that suppresses lung carcinoma cell
The cultivation of human lung cancer cell line A549 cell is to cultivate with RPMI 1640 substratum that contain 10% new-born calf serum, with 5 * 10
5The cell density kind in/hole is implanted 96 porocyte plates, after 24 hours, the small peptide that the present invention relates to is joined in the Tissue Culture Plate according to different concentration, with isopyknic PBS is control group, 24, count with cell counting count board respectively after 48 hours, administration group and control group compare, and the inhibiting rate that obtains lung carcinoma cell reaches 76%.
Embodiment 7
Apoptosis of tumor cells DNA ladder test (the synthetic small peptide that the present invention relates to: Ile-Leu-Pro-Ser-Ala-Ala-Lys)
Leukemia HL-60 cell (5 * 10
5) and the small peptide that adds phosphate group in RPMI 1640 substratum that contain 10% new-born calf serum, co-cultivation 24 hours, resuspended in the buffer system of 50 μ l then, in each sample, add RNase A and Proteinase K respectively, under the temperature of 37 degree, hatched 1 hour respectively, under the temperature of 50 degree, hatching 1 and a half hours.Use EB (ethidium bromide) dyeing then, run agarose electrophoresis, under fluorescent microscope, observe, can observe the tumour cell that apoptosis takes place easily.
Nucleotide or aminoacid sequence table
＜110〉Li Hao
＜120〉a kind of small peptide and application thereof of anticancer growth
<160>2
<210>1
<211>7
<212>PRT
＜213〉artificial sequence
<220>
＜223〉J represented amino acid Lys, Thr or Ile; B represented amino acid Pro or Leu; O represented amino acid Ser or Ala.
<400>1
J-Leu-B-Ser-O-Ala-Lys
<210>2
<211>21
<212>DNA
＜213〉artificial sequence
<220>
＜223〉h represents Nucleotide T, A or C; M represents Nucleotide T or C; N represents Nucleotide T or A.
<400>2
aha?ctg?cmt?tca?nct?gcc?aaa
Claims (5)
1. the small peptide of anticancer growth, it is characterized in that: the aminoacid sequence of forming small peptide is as follows:
Lys-Leu-Pro-Ser-Ser-Ala-Lys or
Thr-Leu-Pro-Ser-Ala-Ala-Lys or
Ile-Leu-Leu-Ser-Ser-Ala-Lys or
Ile-Leu-Pro-Ser-Ala-Ala-Lys or
Gla-Ile-Leu-Pro-Ser-Ala-Ala-Lys or
Leu-Pro-Ser-Ser-Ala。
2. a coding is according to the Nucleotide of the described small peptide of claim 1.
3. the small peptide preparation of an anticancer growth as claimed in claim 1 has the leukemia for the treatment of all kinds of sick cell hyperplasia of non-noumenal tumour people medullary system and causing, the cancer of treatment people noumenal tumour cancer cell multiplication, the application of inhibition hypertension drug.
4. the Nucleotide preparation of the small peptide of an anticancer growth as claimed in claim 2 has the leukemia for the treatment of all kinds of sick cell hyperplasia of non-noumenal tumour people medullary system and causing, the cancer of treatment people noumenal tumour cancer cell multiplication, the application of inhibition hypertension drug.
5. application as the small peptide of claim 3 or 4 described anticancer growths, it is characterized in that: described small peptide or Nucleotide are used to prepare the application that has as the medicine of proteinase inhibitor.
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