WO2017007204A1 - Système de détection de virus résistant à un agent antiviral - Google Patents

Système de détection de virus résistant à un agent antiviral Download PDF

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WO2017007204A1
WO2017007204A1 PCT/KR2016/007191 KR2016007191W WO2017007204A1 WO 2017007204 A1 WO2017007204 A1 WO 2017007204A1 KR 2016007191 W KR2016007191 W KR 2016007191W WO 2017007204 A1 WO2017007204 A1 WO 2017007204A1
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oseltamivir
formula
influenza virus
nanoparticles
mutation
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PCT/KR2016/007191
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English (en)
Korean (ko)
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정주연
임은경
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한국생명공학연구원
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Priority claimed from KR1020160048823A external-priority patent/KR101788454B1/ko
Application filed by 한국생명공학연구원 filed Critical 한국생명공학연구원
Priority to CN201680044850.9A priority Critical patent/CN107850588B/zh
Priority to US15/741,577 priority patent/US10336693B2/en
Publication of WO2017007204A1 publication Critical patent/WO2017007204A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses

Definitions

  • the present invention relates to an antiviral agent-resistant virus detection system.
  • Influenza (flu) is a respiratory disease transmitted by the influenza virus through the respiratory system of humans and animals (birds, pigs, dogs, horses, etc.). Human influenza occurs in 10-20% of the world's population each year, and is highly contagious and tends to spread on a global scale every year. Symptoms of influenza include respiratory diseases such as high fever, headache, muscle pain, sore throat, sore throat, and cough, and in severe cases, death of the elderly, chronic disease holders, and the like.
  • influenza infections are suspected, they should be treated promptly to prevent the development of dangerous situations and to prevent further transmission to others.
  • oseltamivir phosphate Tamiflu
  • Methods for distinguishing viruses have been reported in a number of documents, for example Marin MJ et al. Discloses a method for distinguishing between human influenza virus and avian influenza virus.
  • no effective method has been developed to determine whether a patient suspected of influenza infection has been infected with oseltamivir resistant virus.
  • Non-Patent Document 1 Marin MJ et al. (Glyconanoparticles for the plasmonic detection and discrimination between human and avian influenza, Org Biomol Chem. 2013 Nov 7; 11 (41): 7101-7)
  • the present invention aims to provide a oseltamivir derivative compound, preferably oseltamivir hexylthiol or oseltamivir hexylamine, which is a novel compound that can be used for the detection of oseltamivir resistant virus.
  • An object of the present invention is to provide a nanoparticle for detecting oseltamivir resistant virus in which the oseltamivir derivative compound, preferably oseltamivir hexylthiol or oseltamivir hexylamine is bound.
  • the oseltamivir derivative compound preferably oseltamivir hexylthiol or oseltamivir hexylamine is bound.
  • An object of the present invention is to provide a method for detecting a virus exhibiting resistance to oseltamivir using the nanoparticles.
  • An object of the present invention is to provide a kit for detecting oseltamivir resistant virus comprising the nanoparticles.
  • the present invention provides a method for treating influenza by detecting a virus that is resistant to oseltamivir and administering a therapeutically effective amount of oseltamivir phosphate in a subject that does not contain a virus that is resistant to oseltamivir using the nanoparticles. To provide.
  • the present invention provides an oseltamivir derivative compound represented by the following Chemical Formula 1.
  • R 1 is thiol ( ) Or amine ( )being.
  • the oseltamivir derivative compound is oseltamivir hexylthiol represented by Formula 2 or oseltamivir hexylamine represented by Formula 3 below.
  • the present invention provides a nanoparticle for detecting oseltamivir resistant influenza virus, to which an oseltamivir derivative compound represented by Chemical Formula 1 is bound.
  • the present invention provides nanoparticles for detecting oseltamivir resistant influenza virus, in which oseltamivir hexylthiol represented by Formula 2 or oseltamivir hexylamine represented by Formula 3 is combined.
  • Nanoparticles of the present invention may be any nanoparticles that can be identified by the naked eye or absorption / fluorescence equipment as particles having a diameter of 1 to 100 nanometers, for example, gold nanoparticles, silver nanoparticles, fluorescent nanoparticles, Fluorescent dyes;
  • the gold nanoparticles and silver nanoparticles refer to particles of various shapes (spherical, polygonal, etc.) having a diameter of 100 nanometers or less.
  • the fluorescent nanoparticles are nanoparticles of 100 nanometers or less, which exhibit fluorescence properties, and even if the same material is used, the fluorescence wavelength varies depending on the size of the particles, thereby obtaining fluorescence in various wavelength bands.
  • fluorescent nanoparticles include various nanoparticles containing fluorescent dyes and quantum dots (quantum dot particles), and those consisting of a core having a size of about 2 to 10 nm and a shell composed mainly of ZnS.
  • Group II-VI or III-V compounds forming the quantum dots are, for example, CdSe, CdSe / ZnS, CdTe / CdS, CdTe / CdTe, ZnSe / ZnS, ZnTe / ZnSe, PbSe, PbS InAs, InP, InGaP, InGaP / It may be selected from the group consisting of ZnS and HgTe (in the form of a single core or core / shell).
  • Fluorescent dyes are for example fluorescent organic molecules (e.g., pyrene or derivatives thereof), cyanine, Cy series, Alexa Fluor series, BODIPY series, DY series, Rhodamine or derivatives thereof, Fluorescein or derivatives thereof, coumarin or derivatives thereof, Acridine homodimer or derivatives thereof, Acridine Orange or thereof Derivatives, 7-aminoactinomycin D (7-AAD) or derivatives thereof, actinomycin D or derivatives thereof, ACMA, 9-amino-6-chloro-2 -methoxyacridine or derivatives thereof, DAPI or derivatives thereof, dihydroethidium or derivatives thereof, ethidium bromide or derivatives thereof, ethidium homodimer-1 or EthD-1 this Derivatives, ethidium homodimer-2 (EthD-2) or derivatives thereof, ethidium monoazide or derivatives thereof, hexidium iodide or derivatives thereof
  • the nanoparticles may be gold nanoparticles, but is not limited thereto.
  • Oseltamivir resistant influenza virus is commonly known to undergo mutation of H275Y. Meanwhile, in the art, H275Y may also be described as H274Y depending on the manner of expression, and mutations of H274Y and H275Y are treated as being substantially the same. Hereinafter, the H275Y mutation is used herein to have the same meaning as H274Y.
  • Oseltamivir binds to the influenza virus and kills the virus in a way that reduces neuraminidase (NA) activity. When the H275Y mutation occurs, oseltamivir is difficult to bind to the virus.
  • NA neuraminidase
  • the oseltamivir hexylamine or oseltamivir hexylthiol bound to the nanoparticles of the present invention binds with a binding force about 1000 times stronger to the virus showing resistance to oseltamivir due to H275Y mutation than the oseltamivir sensitive virus.
  • a detection method using a compound that binds to oseltamivir sensitive virus but not to oseltamivir resistant virus only reveal whether or not oseltamivir susceptible virus is present in the sample, such as the presence of other pathogens other than the influenza virus, the presence of other serotype or mutant strains of influenza, or the absence of the pathogen.
  • oseltamivir resistant virus was indistinguishable from the presence of oseltamivir resistant virus, and the disadvantage of having to further confirm the presence of oseltamivir resistant virus in a sample using other means such as specific antibodies and genetic analysis. there was.
  • the presence of oseltamivir susceptible virus can be immediately confirmed, which enables accurate and simple detection compared to the conventional methods.
  • the present invention provides a method for detecting oseltamivir resistant influenza virus using the nanoparticles.
  • nanoparticles of the present invention are bound to a virus can be confirmed by visually comparing the colors (colorimetric method) or by absorbance measurement. Depending on the type and concentration of the nanoparticles used, and the amount of virus contained in the sample may vary, a person skilled in the art can easily distinguish between the presence and absence of oseltamivir resistant influenza virus in the sample. For example, when the nanoparticles of the present invention are treated with oseltamivir resistant influenza virus, as shown in the upper right of FIG.
  • the concentration of the treated nanoparticles increases, the color becomes significantly darker (virus and
  • the nanoparticles of the present invention are treated with the oseltamivir susceptible influenza virus, it can be seen that light colors appear even when the concentration of the nanoparticles is increased.
  • the method of the present invention comprises the steps of: 1) contacting a sample isolated from a subject with oseltamivir hexylthiol represented by formula (2) or oseltamivir hexylamine represented by formula (3). step; 2) When the same color that appears when the nanoparticle is contacted with a sample containing oseltamivir resistant influenza virus appears in the sample of step 1), it is determined that oseltamivir resistant influenza virus is present in the sample. Steps.
  • “same color” means a color that can be regarded as substantially the same even if there are slight differences in chroma, brightness, and hue in reaction conditions, sample conditions, and the like. Means.
  • the method of the present invention 1) a sample isolated from the subject and oseltamivir hexylthiol represented by the formula (2) or oseltamivir hexylamine represented by the formula (3) and Contacting; 2) If a color different from the color that appears when the nanoparticle is contacted with a sample without oseltamivir resistant influenza virus appears in the sample of step 1), it is determined that oseltamivir resistant influenza virus is present in the sample. It includes a step.
  • the subject may be a human or other animal, such as a bird or a mammal.
  • the sample may be whole blood, serum, plasma, blood cells, endothelial cells, tissue biopsy, lymph, ascites fluid, interstitial fluid, bone marrow, cerebrospinal fluid (CSF), semen, saliva, mucus, sputum, sweat or urine.
  • CSF cerebrospinal fluid
  • the present invention provides a kit for detecting oseltamivir resistant influenza virus comprising the nanoparticles.
  • the kit of the present invention may further include other items necessary for detection, and may further include instructions for use.
  • the detection kit of the present invention can be implemented in various forms.
  • a detection solution kit a rapid kit (a small amount of sample dropped into the kit using a lab-on-a-chip), or the sample can be moved on the kit to quickly check the results.
  • a rapid kit a small amount of sample dropped into the kit using a lab-on-a-chip
  • the sample can be moved on the kit to quickly check the results.
  • the detection kit of the present invention may be a rapid diagnostic kit in the form of a diagnostic strip.
  • the detection kit of the present invention includes a sample pad, a conjugate pad, a nitrocelluose membrane, and an adsorption pad.
  • the conjugate pad is supported by oseltamivir hexylthiol-gold nanoparticles or oseltamivir hexylamine-gold nanoparticles,
  • the oseltamivir hexylthiol-gold nanoparticles or oseltamivir hexylamine-gold nanoparticles supported on the conjugate pad are developed together with the sample into the nitrocellulose membrane and the adsorption pad.
  • the nitrocellulose membrane is provided with a control line and a test ine separated from each other.
  • control line is fixed neuramiminids of oseltamivir resistant influenza virus comprising H275Y mutation or oseltamivir resistant influenza virus comprising H275Y mutation
  • test line is oseltamivir represented by Formula 2 Hexylthiol or oseltamivir hexylamine represented by Formula 3 may be fixed.
  • the present invention provides a method for detecting oseltamivir resistant influenza virus using the detection kit.
  • the method is
  • the color change appears only in the control line when the oseltamivir resistant influenza virus is not present in the sample, but the color change appears in both the control line and the test line when present.
  • the degree of color change of the test line is large, it can be determined that the amount of oseltamivir resistant influenza virus contained in the sample is large.
  • a method of treating influenza comprising administering a therapeutically effective amount of oseltamivir phosphate to a subject for which no oseltamivir resistant influenza virus is detected or containing a trace amount of oseltamivir resistant influenza virus.
  • sample without oseltamivir resistant influenza virus or containing a trace amount of oseltamivir resistant influenza virus is free of oseltamivir resistant influenza virus or the level at which oseltamivir phosphate may have a therapeutic effect in a subject.
  • therapeutically effective amount is a reasonable oseltamivir phosphate dosage applicable to any medical treatment, and refers to the amount of therapeutic agent that is statistically related to a particular therapeutic effect when administered to a population of subjects.
  • the detection kit of the present invention is not limited to the above.
  • the oseltamivir analogs of the present invention and the nanoparticles to which the analogs bind are strongly bound to the oseltamivir resistant influenza virus, so that the oseltamivir resistant influenza virus can be detected quickly and conveniently with the naked eye. Therefore, it can be useful to plan treatment of patients who are infected with influenza virus quickly.
  • Figure 1 confirms the degree of oseltamivir hexylamine and oseltamivir hexylthiol inhibit the neuraminidase enzyme activity of oseltamivir-sensitive and oseltamivir resistant virus at the virus level.
  • FIG. 2 is a graph showing the results obtained by treating oseltamivir analogues-gold nanoparticles with oseltamivir-sensitive virus and oseltamivir-resistant virus, respectively, and monitoring the absorbance.
  • Figure 3 is a schematic diagram showing the binding mode of oseltamivir hexylamine and oseltamivir hexylthiol and oseltamivir-sensitive virus and oseltamivir resistant virus of the present invention.
  • ⁇ G bind was about 250 times higher for oseltamivir resistant virus.
  • FIG. 5 is a graph showing the results obtained by treating oseltamivir hexylthiol-bound nanoparticles with oseltamivir-sensitive virus and oseltamivir-resistant virus, respectively, and monitoring the absorbance.
  • Figure 6 is a schematic diagram of the rapid kit and configuration for the detection of antiviral resistant virus prepared using the oseltamivir analog-gold nanoparticles of the present invention.
  • Oseltamivir hexylthiol was synthesized with the following scheme.
  • the numbers indicated in parentheses after the compound names refer to numbers indicated at the bottom of the compound in the following scheme.
  • the oseltamivir hexylthiol is represented by the following formula (2).
  • Oseltamivir hexylamine was synthesized with the following scheme.
  • the numbers indicated in parentheses after the compound names refer to numbers indicated at the bottom of the compound in the following scheme.
  • the oseltamivir hexylamine is represented by the following formula (3).
  • HAuCl 4 solution 1 wt% was added to 100 mL of distilled water and stirred vigorously at 95 ° C. In that state, 1 wt% of sodium citrate (5 mL) was immediately injected slowly and reacted under the same conditions for 30 minutes.
  • Excess sodium citrate was removed by centrifuging 5 mL of the gold nanoparticle solution synthesized in 1-3 at 15000 rpm for 10 minutes. The supernatant was discarded, redispersed in 1 mL of distilled water, and then centrifuged at 15000 rpm for 10 minutes. This process was repeated two more times. In the last step, the supernatant was discarded and 1 mL of oseltamivir hexylamine or oseltamivir hexylthiol (6 mg / mL) dispersed in distilled water was added. And, by voltexing for more than 12 hours, to be bonded to the gold nanoparticles. After centrifugation at 15000 rpm for 20 minutes, the supernatant was removed, and redispersed in 100 ⁇ L of distilled water.
  • NA enzyme activity was measured using NA-FluorTM Influenza Neurmaminidase Assay Kit (AB Applied biosystem, Prod No. 4457091).
  • Solution A was prepared by dissolving Na-fluor (480 ⁇ L) in a working solution (5.52 mL) in the kit.
  • Virus solutions were prepared to contain 100 or 1000 viruses per well, respectively.
  • the wild type (antiviral susceptible virus) used pandemic H1N1 virus (A / 04/2009 / California) (pandemic H1N1), and the mutant type (infectious virus resistant virus) used Influenza A / Korea / 2785/2009 (H275Y mutation).
  • Solution A 50 ⁇ L was added to each well of a 96 well plate, and a virus sample solution was added to each well.
  • Solution C was added to each well prepared at different concentrations by 50 ⁇ L (only distilled water was added in the comparison group). That is, solution A + each virus solution (wild type or mutant type) + solution C was added to each well. After incubation at 37 ° C. for 1 hour, 50 ⁇ L of Na-flour stop buffer solution was added to each well. Fluorescence was measured at Ex: 360 nm and Em: 450 nm to determine NA activity at the protein level. Higher NA enzyme activity means higher fluorescence intensity.
  • Each well of a 96 well plate was prepared to contain 0.1 mg (100 ⁇ g) / well of neuraminidase protein isolated from the wild type or the mutant type, and oseltamivir hexyl synthesized in 1-4 in each well. After adding 100 ⁇ L (1.22 mg of gold ion concentration) to the thiol-bound gold nanoparticles, the absorbance was measured in the 400-750 nm range.
  • the binding energy ( ⁇ G bind ) of the neuramiminidase site of oseltamivir-sensitive virus (wild type) and oseltamivir resistant virus (mutant type) and oseltamivir hexylthiol of the present invention was calculated.
  • the binding energy of oseltamivir hexylthiol to wild type was -24.33 kcal / mol, but the binding energy to mutant type was -27.62 kcal / mol (refer to the schematic diagram of FIG. 3).
  • Example 4 Development and efficacy evaluation of antiviral resistant virus detection system using oseltamivir analogues-gold nanoparticles
  • the oseltamivir analogue-nanoparticle of the present invention binds to the oseltamivir resistant virus with strong binding force, and thus the color change occurs when the nanoparticle is added to the oseltamivir resistant virus.
  • Each well of a 96 well plate was prepared with 0, 10, 100, or 1000 viruses.
  • the wild type (anti-viral susceptible virus) used pandemic H1N1 virus (A / 04/2009 / California) (pandemic H1N1), and the mutant type (anti-viral resistant virus) used Influenza A / Korea / 2785/2009 (H275Y mutation).
  • 100 ⁇ L of oseltamivir hexylthiol-gold nanoparticles prepared in Example 1 (1.22 mg based on gold ion concentration) was added, and then the absorbance was measured in the range of 400-750 nm to determine antiviral sensitivity / resistance. Viruses were detected through color change.
  • oseltamivir analogue-gold nanoparticles prepared in Example 1, a rapid kit for detecting oseltamivir resistant influenza virus was prepared (FIG. 6). Specifically, 3.3 mg / mL of the neuraminidase protein of oseltamivir resistant influenza virus containing a oseltamivir-bound BSA (test line) and an H275Y mutant was prepared using a nitrocellulose membrane. Membrane strips were prepared in 4 mm x 50 mm. Then, oseltamivir hexylthiol-gold nanoparticles were dispensed to the conjugate pad and dried to prepare.
  • the rapid kit of the present invention has a structure in which the oseltamivir hexylthiol-gold nanoparticles of the conjugation pad are developed together with the sample and absorbed by the adsorption pad through the nitrocellulose membrane when the sample is developed through the sample pad. have.
  • Example 5 Using the rapid kit prepared in Example 5, the detection ability of oseltamivir-sensitive / resistive influenza virus was confirmed.
  • a buffer containing no influenza virus was added to the Rapid Kit as a sample, a line appeared only in the control line and no line in the test line.
  • a buffer containing oseltamivir susceptible virus wild type
  • lines also appeared only in the control line.
  • a buffer containing oseltamivir resistant virus (mutant type) was added to the rapid kit, lines appeared in both the control line and the test line (FIG. 7). From the above results, it was verified that the oseltamivir resistant influenza virus can be efficiently detected using the rapid kit including the oseltamivir analog-gold nanoparticles of the present invention.

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Abstract

Un analogue de l'oséltamivir et des nanoparticules ayant l'analogue lié à ces dernières, selon la présente invention, se lient fortement à des virus de la grippe résistant à l'oséltamivir, et ainsi, l'utilisation de ces derniers peut permettre la détection de virus de la grippe résistant à l'oséltamivir rapidement et facilement à l'œil nu. Par conséquent, la présente invention peut être utilisée favorablement pour établir rapidement un programme thérapeutique pour un patient infecté par des virus de la grippe.
PCT/KR2016/007191 2015-07-03 2016-07-04 Système de détection de virus résistant à un agent antiviral WO2017007204A1 (fr)

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CN201680044850.9A CN107850588B (zh) 2015-07-03 2016-07-04 抗病毒剂耐受性病毒的检测系统
US15/741,577 US10336693B2 (en) 2015-07-03 2016-07-04 Antiviral-agent resistant virus detection system

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KR1020160048823A KR101788454B1 (ko) 2015-07-03 2016-04-21 항바이러스제-저항성 바이러스 검출 시스템

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