Antimicrobial peptide AMitP with acid activation property and synthesis and application thereof in preparation of anti-tumor medicaments
An antimicrobial peptide and acid-activated technology, applied in the field of biochemical drugs, can solve problems such as abnormal tumor blood vessels, acidic microenvironment of tumor tissue, and cannot be removed in time, and achieve the effect of improving the selectivity of antimicrobial peptides
Active Publication Date: 2012-10-10
LANZHOU UNIVERSITY
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Problems solved by technology
Studies have shown that due to the rapid metabolism and insufficient oxygen supply of tumor tissue cells, the cells provide energy through glycolysis to produce a large amount of lactic acid, but the abnormal blood vessels of the tumor cannot be cleared in time, which eventually leads to an acidic microenvironment of the tumor tissue
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[0058] The synthesis of the acid-activated antimicrobial peptide AMitP of the present invention will be further illustrated by specific examples below.
[0059] (1) Cys-MitP and its corresponding anionic polypeptide compound Cys-MitP E The solid-phase synthesis of:
[0060] a. Resin pretreatment: Add Rink-Amide-MBHA resin with an amino molar mass of 0.2 mmol into the reactor, add 10 mL of dichloromethane and stir for 30 min to fully swell the resin, and then drain the solvent under reduced pressure.
[0061] b. Deprotection of F-moc: add 10~15mL deprotection reagent into the reactor, stir for 2min, then drain, repeat 4 times to completely remove the Fmoc group, and finally wash with DMF to remove the deprotection reagent; deprotection The reagent is piperidine / DMF=1:4 (V / V).
[0062] c. Condensation: 0.6~0.8 mol Fmoc group-protected amino acid, N-hydroxybenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea-hexa Dissolve fluorophosphate in 3~5mL DMF, then add 1.2~1.6 mol ...
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The invention provides an efficient and low-toxicity acid activated antimicrobial peptide with anti-tumor activity. Antimicrobial peptide MitP is used as a template, lysine (K) in the sequence of the antimicrobial peptide MitP is substituted into glutamic acid (E) and histidine (H), and anionic polypeptide MitPE carrying negative charges under normal physiological conditions is synthesized; and the anionic polypeptide is connected with the antimicrobial peptide MitP through a disulfide bond to form a living antimicrobial peptide compound with acid activation property. The synthesized antimicrobial peptide has obvious acid dependency activity; and the antimicrobial peptide has excellent cell killing activity under acidic conditions, and the cell killing activity of the antimicrobial peptide under the normal physiological conditions is remarkably reduced. The selectivity of the antimicrobial peptide can be improved, injury to normal tissue cells due to the antimicrobial peptide is weakened, the toxic or side effect of the antimicrobial peptide is reduced, and a broad prospect is provided for developing antimicrobial peptide medicaments.
Description
technical field [0001] The invention belongs to the field of biochemical drugs, and relates to a new antimicrobial peptide compound and its synthesis, in particular to an antimicrobial peptide AMitP with acid activation properties and its synthesis method; the invention also relates to the use of the antimicrobial peptide in the preparation of antitumor drugs Applications. Background technique [0002] Tumor is one of the important diseases that threaten human health. Chemotherapy is an effective conventional method of treating tumors or slowing their growth. However, most traditional anticancer drugs have poor selectivity, strong side effects, and multidrug resistance of tumors, which seriously affect the clinical efficacy (Accounts Chem. Res., 2007, 41, 98). Improving selectivity has become a key problem to be solved in the development of antitumor drugs. Therefore, there is an urgent need to develop a class of broad-spectrum, highly selective drugs with new targets and...
Claims
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Login to View More IPC IPC(8): C07K14/00C07K1/20C07K1/06C07K1/04A61K38/16A61P35/00
Inventor 王锐宋竟婧张伟开明张邦治
Owner LANZHOU UNIVERSITY