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Medicine for regulating platelet activity, screening method and application of medicine

A platelet and drug technology, applied in the field of hematology and biomanufacturing, to achieve broad industrialization prospects, easy synthesis and purification, and low immunogenicity

Active Publication Date: 2018-04-24
INST OF ZOOLOGY CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no report on the application of drugs for the regulation of mitophagy in platelets for the storage period of platelets in vitro or the regulation of platelet activity, and because the phenomena and molecular mechanisms of mitophagy and platelet survival are unknown, so by regulating cell mitophagy Screening of drugs that affect platelet storage period in vitro or platelet activity will be beneficial to the development of new drugs with clinical application value

Method used

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  • Medicine for regulating platelet activity, screening method and application of medicine
  • Medicine for regulating platelet activity, screening method and application of medicine
  • Medicine for regulating platelet activity, screening method and application of medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 Hypoxia promotes FUNDC1-dependent mitophagy in platelets in vivo

[0052] We obtained Fundc1 gene knockout mice (F1KO mice for short) from the Sanger Institute (Cambridge, UK), and carried out corresponding identification to prove its Fundc1 gene knockout ability, etc. ( figure 1 a-b). We found that Fundc1 knockout mice also had normal blood and spleen phenotypes ( figure 1 c-f). Next, we exposed the mice to a hypoxic environment with 8% oxygen content for 3 consecutive days, and then isolated platelets from Fundc1 knockout mice and wild-type mice, and detected the expression of mitochondria-related proteins by immunoblotting. Expression level (Tim23 is a molecular marker of mitochondrial outer membrane, Tom20 is a molecular marker of mitochondrial inner membrane), p62 expression level and LC3-II expression level (p62 and LC3-II are biochemical markers of autophagy). We found that in platelets isolated from wild-type mice, the levels of mitochondria-related...

Embodiment 2

[0055] Example 2 Autophagy caused by hypoxia determines the function and quality of mitochondria in vivo

[0056] We synthesized a membrane-permeable peptide that mimics the dephosphorylation and phosphorylation of tyrosine 18 in the LIR domain of FUNDC1. Indeed, a dephosphorylated synthetic peptide (P1: GRKKRRQRRRPQDYESDDESYEVLDLTE) could effectively prevent hypoxia-induced degradation of mitochondrial proteins and p62, and could prevent the conversion of LC-3I to LC3-II in wild-type platelets, while phosphorylated peptide (P2: GRKKRRQRRRPQDYESDDESpYEVLDLTE) does not have this function ( image 3 b). The results of co-immunoprecipitation experiments showed that the P1 peptide effectively inhibited the interaction between FUNDC1 and LC3 in wild-type platelets treated under hypoxic conditions, while the P2 peptide did not ( image 3 a). The above experiments preliminarily indicated that the phosphorylated synthetic peptide P1 could prevent the autophagy of platelet mitochond...

Embodiment 3

[0058] Example 3 Autophagy involved in FUNDC1 can regulate the activity of platelets

[0059] Hypoxia significantly reduced platelet aggregation in wild-type platelets treated with thrombin and ADP, whereas treatment with P1 peptide, but not P2 peptide, reversed this trend ( Figure 4 a-d). On the other hand, platelets derived from Fundc1 knockout mice were treated with ADP and thrombin, and the aggregation ability of platelets was significantly reduced, which may be due to the damage of mitochondrial number ( Figure 4 a-d). Likewise, the ability of ADP- and thrombin-induced platelets to spread on VWF-coated coverslips was inhibited both in hypoxia-treated wild-type platelets and in untreated Fundc1-deficient platelets ( Figure 4 e-h). But the expressions of ADP and thrombin receptors P2Y12 and Par2 and the downstream signaling platelet integrin protein receptor IIbIIIa did not change significantly. Fundc1 insufficiency did not promote apoptosis of platelets (treated wit...

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Abstract

The invention relates to a pharmaceutical composition for regulating platelet activity, a kit as well as a screening method of the pharmaceutical composition and an application of the pharmaceutical composition in preventing or treating platelet survival time shortening related diseases such as thrombotic thrombocytopenic purpura and the like and in prolonging a platelet in-vitro preservation time. The pharmaceutical composition for inhibiting platelet mitochondrial autophagy provided by the invention can inhibit an interaction between FUNDC1 and LC3 in platelet, inhibit the platelet mitochondrial autophagy and keep the activity of the platelet, and the pharmaceutical composition comprises cell-penetrating oligopeptide of an LIR structural domain of the FUNDC1. Particularly, the inventionalso relates to a medicine screening method which takes the interaction between mitochondria FUNDC1 and LC3 as a target; with the application of the method, a medicine capable of inhibiting the interaction between the FUNDC1 and the LC3 and capable of regulating mitochondrial autophagy and platelet activity can be screened out; the medicine is used for preventing or treating the platelet survivaltime shortening related diseases such as thrombotic thrombocytopenic purpura and the like or prolonging the platelet in-vitro preservation time; and the medicine has a good clinical application prospect.

Description

technical field [0001] The invention belongs to the field of hematology and biomanufacturing, and relates to a drug and a drug screening method for regulating platelet activity and prolonging the platelet storage time in vitro. The invention also relates to the use of the drug in protecting platelet activity and prolonging the preservation time of platelet in vitro. Background technique [0002] Mitochondria are important organelles that control cellular energy metabolism and are also the regulatory center of cell apoptosis. Under the stimulation of apoptosis factors, mitochondria release cytochrome C and other apoptosis-related molecules to initiate the process of cell apoptosis. At the same time, mitochondria are also the center of cellular free radical production. In view of these important roles of mitochondria in cell life activities, damaged or unnecessary mitochondria must be effectively removed to ensure the normal life activities of cells. Mitophagy is such a proc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K38/10A61K38/16A61K38/17A01N1/02A61P7/04A61P35/00A61P1/18A61P25/28A61P29/00A61P31/04G01N33/50
CPCA01N1/021A61K38/10A61K38/16A61K38/1709A61K45/00G01N33/5008A01N1/02A61K38/17A61P1/18A61P7/04A61P25/28A61P29/00A61P31/04A61P35/00G01N33/50
Inventor 陈佺张卫林刘垒杜蕾王晓慧王珺
Owner INST OF ZOOLOGY CHINESE ACAD OF SCI
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