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METHOD FOR SCREENING SUBSTANCE HAVING HIGH AFFINITY FOR TARGET SUBSTANCE NEW

外国特許コード F180009514
整理番号 (S2017-0313-N0)
掲載日 2018年11月2日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2018JP003442
国際公開番号 WO 2018143357
国際出願日 平成30年2月1日(2018.2.1)
国際公開日 平成30年8月9日(2018.8.9)
優先権データ
  • 特願2017-016609 (2017.2.1) JP
発明の名称 (英語) METHOD FOR SCREENING SUBSTANCE HAVING HIGH AFFINITY FOR TARGET SUBSTANCE NEW
発明の概要(英語) This method for screening a substance having a high affinity for a target substance includes: a step of preparing a measurement sample in which a sample containing a candidate substance is brought into contact with the target substance; a step in which the measurement sample is subjected to imaging mass spectrometry using matrix assisted laser desorption/ionization (MALDI) with the target substance as a matrix, to identify an ionized molecule; and a step of selecting the identified molecule as being a substance having high affinity for the target substance.
従来技術、競合技術の概要(英語) BACKGROUND ART
In drug development, a huge amount of compound from a library of compounds having the expected therapeutic effect can be effectively selected in important.For this purpose, if the evaluation item is better is simple.For example, a variety of physiologic functions to affect the complexity of the target animal with the individual, by screening the candidate compound than in the case of a therapeutic effect, a simple cell physiology more preferable to be a target.Further, the therapeutic effect are directly involved in the interaction at the molecular level can be analyzed more, a compound having a therapeutic effect for the purpose of more efficiently can be selected.Such as a particular neuropsychiatric disease therapeutic affect a higher function of a living body is described, the action of the individual animal experiments to assess the large amount of time and investment, since the labor is required, a highly reliable evidence based on the obtained evaluation method and a molecular target.
Conventionally, as a method for evaluating the interaction between molecules, such as by immunoprecipitation and Western blot or affinity purification in combination with a detection system such as mass spectrometry, fluorescence resonance energy transfer (FRET) methods such as imaging techniques, surface plasmon resonance analysis and the analysis quantity change, such as nuclear magnetic resonance (NMR) of the high magnetic field such as spectra analysis is generally performed by the.In these methods, a sample of high purity, high quality antibodies, the fabrication of the probe, the isotope label is required and thus, in practice, the cost and labor, time, various constraints in terms of safety is present.For example, in some methods require the detection probe, specific for each target observation for designing a probe, only the interaction between the molecules of interest cannot be measured.In addition, methods which do not use probes to detect, for example, a binding molecule against a target substance such as liquid chromatography-mass spectrometry method that detects, as the pre-processing such as purification of the immunoprecipitation method and is generally, also in this purification step is limited due to the detectable molecule.For this reason, if the search of the binding molecule study, the non-target can be analyzed by a detection system is required.Further, if there is the step of extracting from the living organism, in vitro or refining operation in the living environment is changed or a case where a three-dimensional structure, only a limited location of the living body does not exist in the first place can be difficult to collect the trace molecules such as the problem.
In addition, in the drug development, in recent years, the cause of the disease specific in biological cells, involved in biological cells and in particular targeted to the physiologically active substance, a so-called molecular target agent is currently under development.This is, the cause of the disease to elucidate the molecular level or at the genomic level, disease related to the target material (a compound having a pharmacological effect) pharmaceutical molecular design is carried out from, a pharmaceutical is designed, the greater the effect the treatment of a disease, other diseases further less likely to be acting in biological cells, the effect of reducing the side effects are expected.On the other hand, (1) the cause of the disease at a molecular level or at the genomic level to ascertain the cause of a particular substance, (2) based on the chemical structure, molecular weight of the drug design, are required.However, (1) is also discussed in, (2) any of the days is required and, as a result the power consumption and long-term development.
On the other hand, in recent years, on the biomolecules of the tissue sample to be visualized as a two-dimensional IMS 2 (also referred to as Mass microscopy.) Have been developed for the device.MALDI method (MALDI-IMS) is used in the IMS, such as a tissue section sample to be analyzed, the biomolecule absorbs the laser light and to facilitate the ionization of a low molecular weight compound (matrix) is applied, scanning the laser light is irradiated to, the three-dimensional coordinates 2 of the ions detected at each point on the basis of the image to reconstruct an image.In this method, three-dimensional laser scanning of tissue sections for analysis by 2 as it is, the position information on the tissue sample of the biological molecules can be ionized being maintained.Biological molecule is ionized, and analyzed by time-of-flight mass spectrometer, in accordance with the mass to charge ratio are identified.Thus, in the MALDI-IMS, the distribution of the biomolecules on the tissue sample, between the measurement points by the relative value of the signal intensity of the image can be reduced.As the matrix, ionization of the biomolecules is empirically suitable compounds are used.For example, methoxy 3,5-4-hydroxycinnamic acid, 9-(9AA) such as aminoacridine 50 molecular weight of less than 300 or more is used as the ionic dissociation of the substance, biomolecule on the tissue sample is ionized and a state in which the matrix molecules are coupled and released from the tissue sample, and thereby, in the MALDI-IMS analyzer, mass to charge ratio (m/z) separately for, is identified.
Patent Document 1 is for example, using the MALDI-IMS, the treatment of breast cancer therapeutic agent in the assessment of the effect of a candidate compound has been disclosed a method.In this method, in the breast, a specific molecular species of the phosphatidylcholine lipid metabolism (PC) mammary tissue from there are a large number, the candidate compound has been administered to the subject the presence of the molecular species of phosphatidylcholine in the mammary gland tissue MALDI-IMS is measured by the ratio, there are a number of breast cancer patient and the presence of molecular species in the case where the ratio is low, the candidate compounds are evaluated as effective as treatment of breast cancer.That is, the method, the candidate compound to the subject directly, through metabolism exhibit anti-cancer effects before they are compared, can be used for screening of a candidate substance is naturally on the type of restriction, there has been a limit to the efficiency of screening.In addition, the prior art, using the MALDI-IMS, the intermolecular interaction is not to mention, the in-vivo substance is involved in a method to determine the affinity is not found.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • NATIONAL UNIVERSITY CORPORATION HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE
  • 発明者(英語)
  • SETOU MITSUTOSHI
  • KONDO TAKESHI
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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