JP2018169273A - Peptide adsorption inhibitor - Google Patents
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- JP2018169273A JP2018169273A JP2017066232A JP2017066232A JP2018169273A JP 2018169273 A JP2018169273 A JP 2018169273A JP 2017066232 A JP2017066232 A JP 2017066232A JP 2017066232 A JP2017066232 A JP 2017066232A JP 2018169273 A JP2018169273 A JP 2018169273A
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- 238000001179 sorption measurement Methods 0.000 title abstract description 36
- 108090000765 processed proteins & peptides Proteins 0.000 title abstract description 22
- 239000003112 inhibitor Substances 0.000 title description 2
- 238000003018 immunoassay Methods 0.000 claims abstract description 12
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 239000002888 zwitterionic surfactant Substances 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- ULCUCJFASIJEOE-NPECTJMMSA-N adrenomedullin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)[C@@H](C)O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ULCUCJFASIJEOE-NPECTJMMSA-N 0.000 claims description 8
- 102000004379 Adrenomedullin Human genes 0.000 claims description 7
- 101800004616 Adrenomedullin Proteins 0.000 claims description 7
- 150000001450 anions Chemical class 0.000 claims description 6
- 239000000693 micelle Substances 0.000 claims description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 101800001586 Ghrelin Proteins 0.000 claims description 3
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical group C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 claims description 3
- 125000000962 organic group Chemical group 0.000 claims description 3
- 102000012004 Ghrelin Human genes 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 238000005259 measurement Methods 0.000 abstract description 19
- 239000000243 solution Substances 0.000 abstract description 15
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 abstract description 6
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 abstract description 6
- 229960003237 betaine Drugs 0.000 abstract description 6
- PSBDWGZCVUAZQS-UHFFFAOYSA-N (dimethylsulfonio)acetate Chemical compound C[S+](C)CC([O-])=O PSBDWGZCVUAZQS-UHFFFAOYSA-N 0.000 abstract description 2
- 229940117986 sulfobetaine Drugs 0.000 abstract description 2
- 239000002563 ionic surfactant Substances 0.000 abstract 1
- 239000004094 surface-active agent Substances 0.000 description 17
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- 210000002700 urine Anatomy 0.000 description 13
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- 239000004033 plastic Substances 0.000 description 9
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- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 8
- 101150113268 ghrl gene Proteins 0.000 description 8
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- 238000000034 method Methods 0.000 description 7
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- GUQQBLRVXOUDTN-XOHPMCGNSA-N 3-[dimethyl-[3-[[(4r)-4-[(3r,5s,7r,8r,9s,10s,12s,13r,14s,17r)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]propyl]azaniumyl]-2-hydroxypropane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CC(O)CS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 GUQQBLRVXOUDTN-XOHPMCGNSA-N 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- TUBRCQBRKJXJEA-UHFFFAOYSA-N 3-[hexadecyl(dimethyl)azaniumyl]propane-1-sulfonate Chemical compound CCCCCCCCCCCCCCCC[N+](C)(C)CCCS([O-])(=O)=O TUBRCQBRKJXJEA-UHFFFAOYSA-N 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 239000002736 nonionic surfactant Substances 0.000 description 4
- -1 polypropylene Polymers 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 238000011088 calibration curve Methods 0.000 description 3
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- 239000003599 detergent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- DVEKCXOJTLDBFE-UHFFFAOYSA-N n-dodecyl-n,n-dimethylglycinate Chemical compound CCCCCCCCCCCC[N+](C)(C)CC([O-])=O DVEKCXOJTLDBFE-UHFFFAOYSA-N 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- QZRAABPTWGFNIU-UHFFFAOYSA-N 3-[dimethyl(octyl)azaniumyl]propane-1-sulfonate Chemical compound CCCCCCCC[N+](C)(C)CCCS([O-])(=O)=O QZRAABPTWGFNIU-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
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- 102400000442 Ghrelin-28 Human genes 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
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- 230000002862 amidating effect Effects 0.000 description 2
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- DVEKCXOJTLDBFE-UHFFFAOYSA-O carboxymethyl-dodecyl-dimethylazanium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC(O)=O DVEKCXOJTLDBFE-UHFFFAOYSA-O 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- IZWSFJTYBVKZNK-UHFFFAOYSA-N lauryl sulfobetaine Chemical compound CCCCCCCCCCCC[N+](C)(C)CCCS([O-])(=O)=O IZWSFJTYBVKZNK-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
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- 102000014171 Milk Proteins Human genes 0.000 description 1
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- 239000004793 Polystyrene Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- MRUAUOIMASANKQ-UHFFFAOYSA-N cocamidopropyl betaine Chemical compound CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=O MRUAUOIMASANKQ-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
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- 210000003296 saliva Anatomy 0.000 description 1
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- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
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- Investigating Or Analysing Biological Materials (AREA)
Abstract
Description
本発明は、ペプチド吸着抑制剤に関する。 The present invention relates to a peptide adsorption inhibitor.
タンパク質、ペプチドの吸着は、酵素による分解と共に、試料中の濃度変動の大きな要因の一つである。一般的にタンパク質、ペプチドの吸着抑制のために、ｂｏｖｉｎｅ ｓｅｒｕｍ ａｌｂｕｍｉｎ（ＢＳＡ）や乳タンパク質等のタンパク質や界面活性剤が使用される。プラスチック製器具に対しては、タンパク質は疎水的に吸着すると考えられており、疎水的吸着を抑制するために、非イオン性界面活性剤の使用が一般的に行われる。非特許文献１では、検量線用試料の溶液には、ＢＳＡ等に加え、非イオン性界面活性剤のＴｒｉｔｏｎＸ−１００が使用されている。 Adsorption of proteins and peptides is one of the major factors of concentration fluctuations in samples as well as enzymatic degradation. Generally, proteins and surfactants such as bovine serum albumin (BSA) and milk protein are used to suppress adsorption of proteins and peptides. For plastic instruments, proteins are believed to adsorb hydrophobically, and non-ionic surfactants are commonly used to suppress hydrophobic adsorption. In Non-Patent Document 1, TritonX-100, a nonionic surfactant, is used in addition to BSA and the like for the solution of the calibration curve sample.
また、尿はタンパク質量が少ないことから、目的タンパク質が器具へ吸着しやすい。そのため、サンプルの取り扱い方法により、目的タンパク質が器具に吸着することによる測定精度低下が問題となる。器具への吸着を抑制する方法として、親水化等の表面処理をした器具を使用する方法が考えられるが、コストが高くなるという問題がある。そのため、ペプチドの器具への吸着を簡便な方法で抑制し、正確に測定できる定量方法が必要とされている。 Moreover, since urine has a small amount of protein, the target protein is likely to be adsorbed to the instrument. Therefore, depending on how the sample is handled, there is a problem of a decrease in measurement accuracy due to the target protein adsorbing to the instrument. As a method for suppressing the adsorption to the device, a method using a surface-treated device such as hydrophilization can be considered, but there is a problem that the cost increases. Therefore, there is a need for a quantitative method that can suppress the adsorption of the peptide to the instrument by a simple method and accurately measure the peptide.
そこで本発明は、ペプチドの器具への吸着を抑制する手段を提供し、測定精度の向上、検体の取り扱いの簡便化を目的とする。 Therefore, the present invention provides means for suppressing the adsorption of peptides to the instrument, and aims to improve measurement accuracy and simplify the handling of specimens.
上記課題に鑑みてなされた本発明は、以下の態様を包含する：
（１）ベタイン型又はスルホベタイン型の両性イオン性界面活性剤を、免疫測定用試料に対して臨界ミセル濃度（ＣＭＣ）の０．１〜２．０倍含有する水溶液組成物。
（２）免疫測定の対象がグレリン又はアドレノメデュリンであることを特徴とする（１）に記載の水溶液組成物。
（３）前記両性イオン性界面活性剤が下記一般式（１）で示されるベタイン型又はスルホベタイン型の両性イオン性界面活性剤であることを特徴とする（１）又は（２）に記載の水溶液組成物。
The present invention made in view of the above problems includes the following aspects:
(1) An aqueous solution composition containing a betaine-type or sulfobetaine-type zwitterionic surfactant in an amount of 0.1 to 2.0 times the critical micelle concentration (CMC) relative to a sample for immunoassay.
(2) The aqueous solution composition according to (1), wherein the target of immunoassay is ghrelin or adrenomedullin.
(3) The zwitterionic surfactant is a betaine-type or sulfobetaine-type zwitterionic surfactant represented by the following general formula (1), (1) or (2) Aqueous solution composition.
（式（１）中、Ｒ１は、炭素数１０〜１６のアルキル基又は下記一般式（２）で示される有機基である。Ｒ２及びＲ３は、炭素数９以下の直鎖アルキル基であって、それぞれが同一であってもよく、異なっていてもよい。Ｒ４は、炭素数１〜３のアルキル基又はアルコールである。Ｙ−は、カルボン酸型アニオン（―ＣＯＯ―）又はスルホン酸型アニオン（―ＳＯ３ ―）である。） (In formula (1), R 1 is an alkyl group having 10 to 16 carbon atoms or an organic group represented by the following general formula (2). R 2 and R 3 are linear alkyl groups having 9 or less carbon atoms. And R 4 is an alkyl group having 1 to 3 carbon atoms or an alcohol, and Y − is a carboxylic acid type anion (—COO − ) or This is a sulfonic acid type anion (—SO 3 — ).)
（式（２）中、Ｒ５は、炭素数３以下のアルキル基である。） (In Formula (2), R 5 is an alkyl group having 3 or less carbon atoms.)
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明者らはペプチドの吸着を抑制するため、界面活性剤を添加することを検討した結果、ベタイン型又はスルホベタイン型の両性イオン性界面活性剤にペプチドの測定器具への吸着を抑制する効果があることを見出した。 As a result of studying addition of a surfactant to suppress the adsorption of the peptide, the present inventors have confirmed that the betaine-type or sulfobetaine-type zwitterionic surfactant suppresses the adsorption of the peptide to the measuring instrument. Found that there is.
なお、本発明における「測定器具」とは、ペプチド測定において、検体採取から測定まで、ペプチドを含む試料が接触する器具をいう。具体的には、採血管、採尿容器、チューブ等の容器等が挙げられる。「プラスチック製器具」とは、表面がプラスチック加工されているものも含む。具体的には、プラスチック製チューブ、採尿用カップ等が挙げられる。「プラスチック」とは、合成樹脂が大部分である高分子物質を主原料として人工的に有用な形状に形作られた固体であり、一般には、ポリプロピレン、ポリスチレン、ポリエチレン製の器具が多く使用されている。 The “measuring instrument” in the present invention refers to an instrument that contacts a sample containing a peptide from sample collection to measurement in peptide measurement. Specific examples include blood collection tubes, urine collection containers, and containers such as tubes. “Plastic instruments” include those whose surfaces are processed with plastic. Specific examples include a plastic tube and a urine collection cup. “Plastic” is a solid that is artificially formed into a useful shape using a high-molecular-weight material consisting mostly of synthetic resins as the main raw material. Generally, equipment made of polypropylene, polystyrene, or polyethylene is often used. Yes.
本発明における免疫測定用試料とは、抗体と抗原との反応を利用した定量法である免疫測定に必要な検量線用試料と、測定対象となる生体試料である。生体試料としては、例えば、血液、血清、血漿、尿、唾液、組織液などが挙げられる。 The sample for immunoassay in the present invention is a sample for a calibration curve necessary for immunoassay, which is a quantification method using a reaction between an antibody and an antigen, and a biological sample to be measured. Examples of the biological sample include blood, serum, plasma, urine, saliva, tissue fluid, and the like.
本発明で用いられるベタイン型又はスルホベタイン型の両性イオン性界面活性剤は、
３−（Ｎ，Ｎ−ジメチルオクチルアンモニオ）プロパンスルホン酸 分子内塩（ＳＢ３−８）、ココアミドプロピルベタイン、ジメチルドデシルベタイン、ＣＨＡＰＳ、ＣＨＡＰＳＯ、Ｎ，Ｎ−ジメチル−Ｎ−ドデシルグリシンベタイン（ＥＭＰＩＧＥＮ（登録商標） ＢＢ ｄｅｔｅｒｇｅｎｔ）、３−（Ｎ，Ｎ−ジメチルヘキサデシルアンモニオ）プロパンスルホン酸（ＳＢ３−１６）、Ｎ‐ドデシル‐Ｎ，Ｎ‐ジメチル‐１‐アンモニオ‐３‐プロパンスルホナート、ラウリン酸アミドプロピルジメチルアミノ酢酸ベタイン等が挙げられる。
The betaine type or sulfobetaine type zwitterionic surfactant used in the present invention is:
3- (N, N-dimethyloctylammonio) propanesulfonic acid inner salt (SB3-8), cocoamidopropylbetaine, dimethyldodecylbetaine, CHAPS, CHAPSO, N, N-dimethyl-N-dodecylglycine betaine (EMPIGEN) (Registered trademark) BB detergent), 3- (N, N-dimethylhexadecylammonio) propanesulfonic acid (SB3-16), N-dodecyl-N, N-dimethyl-1-ammonio-3-propanesulfonate, And lauric acid amidopropyldimethylaminoacetic acid betaine.
上述した両性イオン性界面活性剤の中でも、下記一般式（１）で示される構造体が好ましい。 Among the zwitterionic surfactants described above, a structure represented by the following general formula (1) is preferable.
（式（１）中、Ｒ１は、炭素数１０〜１６のアルキル基又は下記一般式（１）で示される有機基である。Ｒ２及びＲ３は、炭素数９以下の直鎖アルキル基であって、それぞれが同一であってもよく、異なっていてもよい。Ｒ４は、炭素数１〜３のアルキル基又はアルコールである。Ｙ−は、カルボン酸型アニオン（―ＣＯＯ―）又はスルホン酸型アニオン（―ＳＯ３ ―）である。） (In formula (1), R 1 is an alkyl group having 10 to 16 carbon atoms or an organic group represented by the following general formula (1). R 2 and R 3 are linear alkyl groups having 9 or less carbon atoms. And R 4 is an alkyl group having 1 to 3 carbon atoms or an alcohol, and Y − is a carboxylic acid type anion (—COO − ) or This is a sulfonic acid type anion (—SO 3 — ).)
（式（２）中、Ｒ５は、炭素数３以下のアルキル基である。） (In Formula (2), R 5 is an alkyl group having 3 or less carbon atoms.)
具体的には、ジメチルドデシルベタイン、ＣＨＡＰＳ、ＣＨＡＰＳＯ、Ｎ，Ｎ−ジメチル−Ｎ−ドデシルグリシンベタイン（ＥＭＰＩＧＥＮ（登録商標） ＢＢ ｄｅｔｅｒｇｅｎｔ）、３−（Ｎ，Ｎ−ジメチルヘキサデシルアンモニオ）プロパンスルホン酸（ＳＢ３−１６）、Ｎ‐ドデシル‐Ｎ，Ｎ‐ジメチル‐１‐アンモニオ‐３‐プロパンスルホナート等が挙げられる。 Specifically, dimethyldodecylbetaine, CHAPS, CHAPSO, N, N-dimethyl-N-dodecylglycine betaine (EMPGEN (registered trademark) BB detergent), 3- (N, N-dimethylhexadecylammonio) propanesulfonic acid (SB3-16), N-dodecyl-N, N-dimethyl-1-ammonio-3-propanesulfonate and the like.
本発明において、両性イオン性界面活性剤は、１種類、もしくは複数種類の界面活性剤を併用してもよい。非イオン、陰イオン、陽イオン性界面活性剤等と併用してもよいが、本発明の効果が十分に得られなくなるおそれがあるため、微量に留めておくことが好ましい。界面活性剤濃度は一定濃度以上であれば吸着を抑制可能であるが、定量方法を阻害することがあるので、免疫測定用試料に対して臨界ミセル濃度（ＣＭＣ）の０．１〜２．０倍である必要がある。界面活性剤濃度が免疫測定用試料に対してＣＭＣの２．０倍を超えると、抗体を用いた免疫測定で定量する場合などに抗原抗体反応を阻害するおそれがある。 In the present invention, as the zwitterionic surfactant, one type or a plurality of types of surfactants may be used in combination. Although it may be used in combination with a nonionic, anionic, cationic surfactant, or the like, it is preferable to keep it in a very small amount because the effects of the present invention may not be sufficiently obtained. Adsorption can be suppressed if the surfactant concentration is a certain concentration or more, but the quantitative method may be inhibited. Therefore, the critical micelle concentration (CMC) of 0.1 to 2.0 with respect to the sample for immunoassay. Need to be doubled. If the surfactant concentration exceeds 2.0 times CMC with respect to the sample for immunoassay, the antigen-antibody reaction may be inhibited when quantified by immunoassay using an antibody.
本発明の測定対象としては、グレリン（Ｇｈｒｌ）又はアドレノメデュリン（ＡＭ）が好ましい。Ｇｈｒｌは、２８残基のアミノ酸からなるペプチドであり、成長ホルモン分泌促進作用、摂食促進作用、エネルギー代謝調節作用、血圧降下等の循環調節作用など多彩な生理活性作用をもつ。ＡＭは、５２残基のアミノ酸からなるペプチドであり、強力な血管拡張性の降圧作用を有している。ＡＭは前駆体より中間体のペプチド（ＡＭ−Ｇｌｙ）が生合成され、アミド化酵素により活性を有する成熟型ペプチド（ｍＡＭ）生合成される。本発明で使用される「ｍＡＭ測定」とは、アミド化酵素により活性を有する末端がＮＨ２である成熟型ペプチド（ｍＡＭ）を測定するものをいい、「ｔＡＭ測定」とは、末端がＧｌｙである中間体のペプチド（ＡＭ−Ｇｌｙ）と成熟型ペプチド（ｍＡＭ）の両方を測定するものをいう。 As a measuring object of the present invention, ghrelin (Ghrl) or adrenomedullin (AM) is preferable. Ghrl is a peptide composed of 28 amino acid residues, and has various physiological activities such as growth hormone secretion promoting action, feeding promoting action, energy metabolism regulating action, and circulation regulating action such as blood pressure lowering. AM is a peptide consisting of 52 amino acids and has a strong vasodilatory antihypertensive action. In AM, an intermediate peptide (AM-Gly) is biosynthesized from a precursor, and an active mature peptide (mAM) is biosynthesized by an amidating enzyme. The “mAM measurement” used in the present invention refers to a measurement of a mature peptide (mAM) having a terminal NH 2 having activity by an amidating enzyme, and the “tAM measurement” is a terminal having Gly. It refers to measuring both an intermediate peptide (AM-Gly) and a mature peptide (mAM).
本発明によれば、ペプチドの測定器具への吸着を抑制することにより、測定試薬で使用する検量線用試料の安定化が可能である。また、測定者の検体の取り扱いを容易にし、ペプチドをより正確に定量可能となるため、臨床応用上非常に有用である。 According to the present invention, it is possible to stabilize the calibration curve sample used in the measurement reagent by suppressing the adsorption of the peptide to the measurement instrument. In addition, it is very useful for clinical application because it facilitates the handling of the specimen by the measurer and makes it possible to quantify the peptide more accurately.
以下に実施例を示すが、本発明は実施例に記載された例に限られるものではない。なお、以下の実施例で使用したヒト検体は、インフォームドコンセントのもと採取された検体を用い実施した。
また、Ｇｈｒｌ、ｍＡＭ、ｔＡＭ濃度測定は、自動免疫測定装置ＡＩＡシリーズ（東ソー社製）を用いて実施した。
Examples are shown below, but the present invention is not limited to the examples described in the Examples. In addition, the human sample used in the following examples was performed using a sample collected under informed consent.
Ghrl, mAM, and tAM concentrations were measured using an automatic immunoassay device AIA series (manufactured by Tosoh Corporation).
実施例１：各種界面活性剤の効果（ｔＡＭ測定）
リン酸緩衝生理食塩水（ＰＢＳ）に下記の界面活性剤を添加したものを、ベース液とした。プラスチック製器具であるクライオチューブ（ＴＰＰ社製）で、ＰＢＳとベース液にそれぞれｍＡＭ抗原を添加して「処理前液」とした。ｍＡＭ抗原は市販の抗原を使用した（ペプチド研究所、Ａｄｒｅｎｏｍｅｄｕｒｉｎ （ｈｕｍａｎ））。なお、ＣＨＡＰＳ、ＣＨＡＰＳＯ、ＥＭＰＩＧＥＮ（登録商標） ＢＢ ｄｅｔｅｒｇｅｎｔ及びＳＢ３−１６の実験、ＳＤＳ及びＴｗｅｅｎの実験はそれぞれ別の日に行った。
Example 1: Effect of various surfactants (tAM measurement)
A base solution was prepared by adding the following surfactant to phosphate buffered saline (PBS). With a cryotube (manufactured by TPP), which is a plastic instrument, mAM antigens were added to PBS and the base solution, respectively, to obtain a “pretreatment solution”. A commercially available antigen was used as the mAM antigen (Peptide Institute, Adrenomedurin (human)). The CHAPS, CHAPSO, EMPIGEN (registered trademark) BB detergent and SB3-16 experiments, and the SDS and Tween experiments were performed on different days.
（使用材料）
（１）両性イオン性界面活性剤
（１−１）ＣＨＡＰＳ（同仁化学研究所製）（Ｃ３２Ｈ５８Ｎ２Ｏ７Ｓ）（臨界ミセル濃度（ＣＭＣ）：８．００ｍＭ、０．４９２％）
（１−２）ＣＨＡＰＳＯ（同仁化学研究所製）（Ｃ３２Ｈ５８Ｎ２Ｏ８Ｓ）（ＣＭＣ：８．００ｍＭ、０．５０５％）
（１−３）Ｎ，Ｎ−ジメチル−Ｎ−ドデシルグリシンベタイン（ＥＭＰＩＧＥＮ（登録商標） ＢＢ）（シグマ アルドリッチ製）（ＣＨ３（ＣＨ２）８−１４ＣＨ２Ｎ＋（ＣＨ３）２ＣＨ２ＣＯＯ−）（ＣＭＣ：平均１．８５ｍＭ、０．０５１６％）
（１−４）３−（Ｎ，Ｎ−ジメチルヘキサデシルアンモニオ）プロパンスルホン酸（ＳＢ３−１６）（シグマ アルドリッチ製）（ＣＨ３（ＣＨ２）１５Ｎ＋（ＣＨ３）２ＣＨ２ＣＨ２ＣＨ２ＳＯ３ −）（ＣＭＣ：平均０．０３５０ｍＭ、０．００１３７％）
（２）陰イオン性界面活性剤
（２−１）ドデシル硫酸ナトリウム（ＳＤＳ）（和光純薬製）（ＣＭＣ：８．００ｍＭ、０．２３１％）
（３）非イオン性界面活性剤
（３−１）Ｔｗｅｅｎ ＃２０（ナカライテスク製）（ＣＭＣ：０．０６００ｍＭ、０．００７３７％）
(Materials used)
(1) Zwitterionic surfactant (1-1) CHAPS (manufactured by Dojindo Laboratories) (C 32 H 58 N 2 O 7 S) (critical micelle concentration (CMC): 8.00 mM, 0.492%)
(1-2) CHAPSO (manufactured by Dojindo Laboratories) (C 32 H 58 N 2 O 8 S) (CMC: 8.00 mM, 0.505%)
(1-3) N, N-dimethyl-N-dodecylglycine betaine (EMPIGEN (registered trademark) BB) (manufactured by Sigma-Aldrich) (CH 3 (CH 2 ) 8-14 CH 2 N + (CH 3 ) 2 CH 2 COO − ) (CMC: average 1.85 mM, 0.0516%)
(1-4) 3- (N, N-dimethylhexadecylammonio) propanesulfonic acid (SB3-16) (manufactured by Sigma-Aldrich) (CH 3 (CH 2 ) 15 N + (CH 3 ) 2 CH 2 CH 2 CH 2 SO 3 -) (CMC : mean 0.0350mM, 0.00137%)
(2) Anionic surfactant (2-1) Sodium dodecyl sulfate (SDS) (manufactured by Wako Pure Chemical Industries, Ltd.) (CMC: 8.00 mM, 0.231%)
(3) Nonionic surfactant (3-1) Tween # 20 (manufactured by Nacalai Tesque) (CMC: 0.0600 mM, 0.00737%)
（実験手順）
処理前液のｔＡＭ濃度を測定した後、処理前液をプラスチック製器具であるチューブ（ＣＥＬＬＳＴＡＲ（登録商標）ＰＰ遠心管、Ｇｒｅｉｎｅｒ Ｂｉｏ−Ｏｎｅ製）に移し、転倒混和を１０回、５分静置したのち、転倒混和を再び１０回行った「チューブ液」のｔＡＭ濃度を測定した。
(Experimental procedure)
After measuring the tAM concentration of the pre-treatment solution, the pre-treatment solution is transferred to a tube (CELLSTAR (registered trademark) PP centrifuge tube, manufactured by Greiner Bio-One), which is a plastic instrument, and mixed by inversion 10 times for 5 minutes. After that, the tAM concentration of the “tube solution” in which the inversion mixing was repeated 10 times was measured.
界面活性剤を添加することによる測定値の濃度変化（回収率）は、界面活性剤を添加していない処理前液と界面活性剤を添加した処理前液のｔＡＭ濃度により、下記の式で算出した。
（回収率）［％］＝（各界面活性剤を添加した処理前液濃度）／（界面活性剤を添加していない処理前液濃度）
回収率は値が低いと界面活性剤が測定に及ぼす影響、本実施例では抗原抗体反応に及ぼす影響が大きい。すなわち、１００％を基準とし、それよりも値が顕著に低い場合は、界面活性剤が測定を阻害しているといえる。なお、界面活性剤を添加していない処理前液は、測定までの間に器具への吸着がおこり、低値となることがあるため、回収率が１００％を超えることもあり、本発明においては回収率が１００％を超えるとき、本発明の効果を有するものと判定する。
The change in concentration (recovery rate) of the measured value due to the addition of the surfactant is calculated by the following formula using the tAM concentration of the pre-treatment solution without the surfactant and the pre-treatment solution with the surfactant added. did.
(Recovery rate) [%] = (Concentration of liquid before treatment with each surfactant added) / (Concentration of liquid before treatment with no surfactant added)
When the recovery rate is low, the influence of the surfactant on the measurement is large, and in this example, the influence on the antigen-antibody reaction is large. That is, when the value is remarkably lower than 100% as a reference, it can be said that the surfactant inhibits the measurement. In addition, since the pre-treatment solution to which the surfactant is not added is adsorbed to the instrument before measurement and may become a low value, the recovery rate may exceed 100%. Is determined to have the effect of the present invention when the recovery rate exceeds 100%.
チューブに対する吸着抑制能（吸着率）は、処理前液とチューブ液のｍＡＭ濃度を比較し、下記の式で算出した。
（吸着率（チューブ液））［％］＝［（処理前液の濃度）―（チューブ液の濃度）］／（処理前液の濃度）
吸着率は値が低いほど吸着量が少なく、吸着抑制能が高い。例えば、吸着率０％では処理による器材への吸着がないことを示す。吸着率１５％は前述した転倒混和処理により１５％が器材に吸着したことを示す。本発明においては吸着率１５％以下のとき、本発明の効果を有するものと判定する。なお、測定濃度値は、ばらつきがあるため、吸着量が微量の場合、吸着率が０％を下回ることもある。
The adsorption suppression ability (adsorption rate) to the tube was calculated by the following formula by comparing the mAM concentrations of the pre-treatment solution and the tube solution.
(Adsorption rate (tube liquid)) [%] = [(concentration of pre-treatment liquid)-(concentration of tube liquid)] / (concentration of pre-treatment liquid)
The lower the value of the adsorption rate, the smaller the amount of adsorption and the higher the ability to suppress adsorption. For example, an adsorption rate of 0% indicates that there is no adsorption to equipment due to processing. The adsorption rate of 15% indicates that 15% was adsorbed on the equipment by the above-described inversion mixing process. In the present invention, when the adsorption rate is 15% or less, it is determined that the effect of the present invention is obtained. Since the measured concentration value varies, the adsorption rate may be less than 0% when the adsorption amount is very small.
結果を表１に示す。 The results are shown in Table 1.
ベタイン型又はスルホベタイン型の両性イオン性界面活性剤（ＣＨＡＰＳ、ＣＨＡＰＳＯ、ＥＭＰＩＧＥＮ（登録商標） ＢＢ、ＳＢ３−１６）は、回収率が高くチューブへの吸着率も低く、吸着を簡便に抑制することができた。陰イオン性界面活性剤（ＳＤＳ）は吸着率が高かった。非イオン性界面活性剤（Ｔｗｅｅｎ＃２０）は、吸着率は低かったが、回収率が低かった。 Betaine-type or sulfobetaine-type zwitterionic surfactants (CHAPS, CHAPSO, EMPIGEN (registered trademark) BB, SB3-16) have a high recovery rate and a low adsorption rate to the tube, and can easily suppress adsorption. I was able to. The anionic surfactant (SDS) had a high adsorption rate. The nonionic surfactant (Tween # 20) had a low adsorption rate but a low recovery rate.
実施例２：ｍＡＭ、Ｇｈｒｌに対する両性イオン性界面活性剤の効果
実施例１と同様にＰＢＳ、両性イオン性界面活性剤の一つであるＣＨＡＰＳを添加したベース液にｍＡＭ抗原、Ｇｈｒｌ抗原を添加し、プラスチック製器具であるチューブに対する効果を確認した。Ｇｈｒｌ抗原は市販の抗原を使用した（Ｇｈｒｌｅｌｉｎ （Ｈｕｍａｎ））。回収率及び吸着率（濃度はｍＡＭ濃度とＧｈｒｌ濃度である）は実施例１と同様の方法で算出した。
Example 2: Effect of zwitterionic surfactant on mAM and Ghrl As in Example 1, mAM antigen and Ghrl antigen were added to a base solution to which PBS and CHAPS, which is one of zwitterionic surfactants, were added. The effect on the tube, which is a plastic instrument, was confirmed. A commercially available antigen was used as the Ghrl antigen (Ghrellin (Human)). The recovery rate and adsorption rate (concentrations are mAM concentration and Ghrl concentration) were calculated in the same manner as in Example 1.
結果を表２に示す。 The results are shown in Table 2.
ｍＡＭに対して、両性イオン性界面活性剤（ＣＨＡＰＳ）を添加することにより、本発明の効果が得られていることを確認した。Ｇｈｒｌに対しては、界面活性剤未添加でも吸着率は低かったが、両性イオン性界面活性剤を添加することにより、さらに吸着が抑制されることを確認した。 It was confirmed that the effect of the present invention was obtained by adding a zwitterionic surfactant (CHAPS) to mAM. For Ghrl, the adsorption rate was low even when no surfactant was added, but it was confirmed that addition of a zwitterionic surfactant further suppressed the adsorption.
実施例３：各濃度における両性イオン性界面活性剤の効果（ｔＡＭ測定）
ＰＢＳに両性イオン性界面活性剤（ＣＨＡＰＳ）を免疫測定用試料中濃度が０〜１．０％、すなわち、臨界ミセル濃度（ＣＭＣ）の０〜２．０３倍になるよう添加し、ｍＡＭ抗原を約５０ｐＭの濃度となるように添加して処理前液とし、プラスチック製器具であるチューブに対する効果を確認した。回収率及び吸着率は実施例１と同様の方法で算出した。
Example 3: Effect of zwitterionic surfactant at each concentration (tAM measurement)
A zwitterionic surfactant (CHAPS) was added to PBS so that the concentration in the sample for immunoassay was 0 to 1.0%, that is, 0 to 2.03 times the critical micelle concentration (CMC). It added so that it might become a density | concentration of about 50 pM, it was set as the liquid before a process, and the effect with respect to the tube which is a plastic instrument was confirmed. The recovery rate and adsorption rate were calculated in the same manner as in Example 1.
結果を表３に示す。 The results are shown in Table 3.
両性イオン性界面活性剤の終濃度が、臨界ミセル濃度（ＣＭＣ）の ０．０５０８倍以下だと吸着率が高くなってしまい、２．０３倍だと回収率が低下した。 When the final concentration of the zwitterionic surfactant was 0.0508 times or less of the critical micelle concentration (CMC), the adsorption rate increased, and when it was 2.03 times, the recovery rate decreased.
実施例４：両性イオン性界面活性剤の尿での効果
内面ポリエチレンラミネート加工された採尿カップ（伊藤忠リーテイルリンク製）に対する回収率及び吸着率についてｍＡＭ測定、ｔＡＭ測定でそれぞれ確認した。採取した尿をチューブに分けたのち、ＰＢＳ又は各界面活性剤を添加したものを処理前液とした。処理前液を採尿カップに移した「採尿カップ液」について、回収率及び吸着率（チューブ液の濃度を採尿カップ液の濃度に置き換えた。濃度はｍＡＭ濃度とｔＡＭ濃度である。）を実施例１と同様の方法で算出した。ただし、尿中にＡＭが含まれているため、抗原は添加しなかった。
Example 4: Effect of zwitterionic surfactant in urine The recovery rate and adsorption rate for a urine collection cup (manufactured by ITOCHU Lee Taillink Co., Ltd.) subjected to inner surface polyethylene lamination were confirmed by mAM measurement and tAM measurement, respectively. The collected urine was divided into tubes, and PBS or each surfactant added was used as a pretreatment solution. Regarding the “urine collection cup liquid” in which the pretreatment liquid was transferred to the urine collection cup, the recovery rate and the adsorption rate (the concentration of the tube liquid was replaced with the concentration of the urine collection cup liquid. It was calculated by the same method as 1. However, since AM was contained in urine, no antigen was added.
結果を表４に示す。 The results are shown in Table 4.
尿を採尿カップで回収した検体についても、ｍＡＭ測定、ｔＡＭ測定ともにいずれの両性イオン性界面活性剤も本発明の効果が得られていることを確認した。 It was also confirmed that both the zwitterionic surfactants obtained the effects of the present invention for both the mAM measurement and the tAM measurement for the specimen obtained by collecting urine with a urine collection cup.
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