CN101270151B - Peptide medicaments for accelerating medulla hematopoiesis cell proliferation - Google Patents
Peptide medicaments for accelerating medulla hematopoiesis cell proliferation Download PDFInfo
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- CN101270151B CN101270151B CN2008100710325A CN200810071032A CN101270151B CN 101270151 B CN101270151 B CN 101270151B CN 2008100710325 A CN2008100710325 A CN 2008100710325A CN 200810071032 A CN200810071032 A CN 200810071032A CN 101270151 B CN101270151 B CN 101270151B
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Abstract
The present invention provides a peptide drug that can promote the proliferation of marrow hematopoietic cells. The main amino acid sequence of the short peptide fragments, analogs, derivants and variants of the short peptide is larger than or equal to 70 percent, equal to and larger than or equal to 90 percent similar to the main amino acid sequence of the short peptide. The short peptide, nucleotides, short peptide fragments, short peptide analogs, short peptide derivants and short peptide variants are used for the preparation of drugs for treating manifold marrow hematopoietic cell defection diseases, congenital anaemia, aplastic anemia and various hemorrhagic anemia diseases and can be applied to the bone marrow transplantation of leukemia patients, etc., that is, the peptide drug of the present invention can treat pancytopenia caused by hemopoietic stem cell defects.
Description
Technical field
The invention belongs to the biotechnology field of medicaments, the present invention has more specifically related to a kind of peptide medicament that promotes myeloid element propagation.
Background technology
Selecting for use of methods of treatment for anaemia need be determined according to the cause of disease of anaemia, can adopt modal blood transfusion to enrich blood for acute posthemorrhagic anemia, but, just can solve for chronic anaemia and the just not simple blood transfusion of the caused anaemia of hemopoietic function of bone marrow obstacle.
Bone marrow transplantation is one of the method for enriching blood that adopts at present, generally be used in the treatment of enriching blood of aplastic amenia people or leukemia patient, but need join type because be used for the hemopoietic stem cell of bone marrow transplantation, and source and limited, therefore also limited the application of this kind methods of treatment, the source of stem cell is a vital problem, therefore, is expecting and can self clone the appearance of the method for stem cell.
Treat the anaemia except the method for enriching blood such as blood transfusion, bone marrow transplantation, what be used to enrich blood is exactly that medicine is enriched blood.In China the various medicines of enriching blood are arranged, and the most common foremost medicine of enriching blood is exactly a donkey-hide gelatin, donkey-hide gelatin not only has enriching blood, the function of hematopoiesis in addition of stopping blooding, and its remarkable effect is confirmed by over the past thousands of years clinical application.
The class medicine of enriching blood in the world has erythropoietin (EPO), interleukin (IL-11) and granulocyte colony-stimulating factor (GM-CSF).EPO is applied in to promote CFU-E to break up to sophisticated red corpuscle, and IL-11 is used for promoting hematoblastic quantity, and GM-CSF mainly is the effect that promotes progenitor cell proliferation.Such medicine is used for the treatment of the anaemia of marrow hemopoiesis function clinically, and its mode of production mostly is engineered method production, and proteinic amino acid is formed and mostly surpassed 100 amino acid, and molecular weight is bigger.
Polypeptide is to be the biologically active substance that a class of unit relates to various cell functions in the organism with amino acid; and often derive through glycosylation, phosphorylation or acidylate; have safety, side effect is little; consumption is little; characteristics such as diverse in function, high specificity have important effect in the adjusting of cell physiological and metabolic function.
Summary of the invention
The present invention seeks at the problems referred to above, a kind of peptide medicament that promotes myeloid element propagation is provided, such medicine has treatment multiple marrow hemopoiesis stem/progenitor cells defective disease, congenital anemia and aplastic anemia, and various hemorrhagic anemia diseases, also be applied to the treatment etc. of the bone marrow transplantation of leukemia patient, such medicine is a kind of medicine that solves the pancytopenia that the hemopoietic stem cell defective caused, and is the active drug that can effectively solve the disease that the hemopoietic stem cell defective causes.
A kind of peptide medicament that promotes myeloid element propagation 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-Asn-Asp-B-Gly-O-Lys wherein, J represented amino acid Phe or Ile; B represented amino acid Ala or Leu; O represented amino acid Leu or Glu;
＜2〉GCA or GCG AAT GCA GTT GGC CTT AAA
The amino acid main sequence of described small peptide is classified amino acid position fixed chief series as, and its choice of location is at interval arranged corresponding amino acid.
A kind of small peptide fragment that promotes the peptide medicament of myeloid element propagation 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.
A kind of small peptide analogue of the peptide medicament of myeloid element propagation that promotes of the present invention 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.
A kind of small peptide derivative that promotes the peptide medicament of myeloid element propagation 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.
A kind of small peptide variant that promotes the peptide medicament of myeloid element propagation 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.
Small peptide of the present invention, Nucleotide, small peptide fragment, small peptide analogue, small peptide derivative and small peptide variant are used to prepare have treats the caused anemia of all kinds of hematopoietic cells of people's medullary system, diagnosis and detects the generation of anaemia and the application of anaemia occurrence degree medicine.
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, use small peptide of the present invention to promote myeloid element propagation, cellularstructure is normal, has no side effect.Peptide medicament of the present invention has treatment multiple marrow hemopoiesis stem/progenitor cells defective disease, congenital anemia and aplastic anemia, and various hemorrhagic anemia diseases, also be applied to the treatment etc. of the bone marrow transplantation of leukemia patient, such medicine is a kind of medicine that solves the pancytopenia that the hemopoietic stem cell defective caused, and is the active drug that can effectively solve the disease that the hemopoietic stem cell defective causes.
Description of drawings
Fig. 1 is that the small peptide that the present invention relates to promotes the test-results that aplastic amenia people bone marrow nucleated cell is bred.Wherein the calculating of proliferation rate is the ratio of test group and control group, and among the figure, X-coordinate is represented the concentration of the peptide that the present invention relates to, and ordinate zou represents that this peptide promotes the proliferation rate of BMNC.
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, and its choice of location is at interval arranged corresponding amino acid, and for example, the amino acid in the J position has 2 kinds of Phe or Ile; This 2 seed amino acid can be placed in singlely＜1 on the position of J, no matter select wherein anyly, this small peptide still has its original biological activity, be a kind of promotion myeloid element propagation, 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 and have the purposes of medicine that treatment includes but not limited to following disease:
Promote the hematopoiesis class small peptide medicine of myeloid element propagation.For example: treat multiple marrow hemopoiesis stem/progenitor cells defective disease, congenital anemia and aplastic anemia, and various hemorrhagic anemias and thrombopenia disease, also be applied to the treatment etc. of the bone marrow transplantation of leukemia patient, the peptide medicament that just the present invention relates to is a kind of medicine that solves the pancytopenia that the hemopoietic stem cell defective caused.
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 PAM 250 scoring matrixs (Dayhoff, M.Schwartz, R.M.and Orcutt, B.C.Atlas of Protein Structure 1978, the 345-352 known according to the biology information technology field; DeLisi, C.andKanehisa, M.Mathematical Biosciences 1984.69:77-85; Schwartz, R.M.and Dayhoff, M.O.Atlas of ProteinStructure, 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
Promote aplastic amenia people bone marrow nucleated cell propagation (Ile-Asn-Asp-Leu-Gly-Leu-Lys)
People's aplastic amenia human bone marrow cell separates mononuclearcell through lymphocyte separation medium, plants and implants 96 porocyte plates, and the cultivation of cell is to cultivate with the DMEM substratum that contains 10% foetal calf serum, with 10
5The cell density plantation in/hole, simultaneously 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, and experimental result shows this bone marrow nucleated cell under the effect of small peptide medicine, and 3 days short proliferation rate reaches 175%.
Embodiment 2
Promote the morphology after the bone marrow nucleated cell propagation to check (the synthetic small peptide fragment that the present invention relates to, 4 or 5 amino acid: Asn-Asp-Leu-Gly-of intercepting or Asp-Leu-Gly-Leu-Lys in sequence)
The cultivation of bone marrow nucleated cell is to cultivate with the DMEM substratum that contains 10% foetal calf serum, with 10
6After the cell density kind in/hole is implanted 24 porocyte plates, at once 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, 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, the form and the control group of cell are as broad as long, and form is normal, belongs to normal hematopoiesis.
Sequence table
Claims (4)
1. small peptide that promotes the peptide medicament of myeloid element propagation, it is characterized in that: the aminoacid sequence of forming small peptide is as follows:
Ile-Asn-Asp-Leu-Gly-Leu-Lys。
2. a coding is according to the Nucleotide of the described small peptide of claim 1.
3. the small peptide of the peptide medicament of a promotion myeloid element as claimed in claim 1 propagation is used for the treatment of application in the medicine of aplastic anemia in preparation.
4. the Nucleotide of the small peptide of the peptide medicament of a promotion myeloid element as claimed in claim 2 propagation is used for the treatment of application in the medicine of aplastic anemia in preparation.
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| CN2008100710325A CN101270151B (en) | 2008-05-13 | 2008-05-13 | Peptide medicaments for accelerating medulla hematopoiesis cell proliferation |
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| CN2008100710325A CN101270151B (en) | 2008-05-13 | 2008-05-13 | Peptide medicaments for accelerating medulla hematopoiesis cell proliferation |
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| CN101270151A CN101270151A (en) | 2008-09-24 |
| CN101270151B true CN101270151B (en) | 2011-04-06 |
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| CN113952446B (en) * | 2021-09-03 | 2023-12-05 | 河南省医药科学研究院 | Application of bioactive peptide in inhibiting bone marrow toxicity |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1724561A (en) * | 2005-07-21 | 2006-01-25 | 李�昊 | Series peptide for promoting proliferation of bone marrow karyota and bone marrow substrate cell and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1724561A (en) * | 2005-07-21 | 2006-01-25 | 李�昊 | Series peptide for promoting proliferation of bone marrow karyota and bone marrow substrate cell and its application |
Non-Patent Citations (1)
| Title |
|---|
| 李昊等.生物活性肽自动查询预测系统.《生物信息学》.2006,(第4期),176-177和181. * |
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