WO2007085403A2 - Supports réticulables multifonction pour ligands (de faible poids moléculaire), leur utilisation en analytique et procédé de production et de réticulation desdits supports - Google Patents
Supports réticulables multifonction pour ligands (de faible poids moléculaire), leur utilisation en analytique et procédé de production et de réticulation desdits supports Download PDFInfo
- Publication number
- WO2007085403A2 WO2007085403A2 PCT/EP2007/000519 EP2007000519W WO2007085403A2 WO 2007085403 A2 WO2007085403 A2 WO 2007085403A2 EP 2007000519 W EP2007000519 W EP 2007000519W WO 2007085403 A2 WO2007085403 A2 WO 2007085403A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- coupling
- ligands
- carriers
- carrier
- crosslinking
- Prior art date
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Classifications
-
- 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
- G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
Definitions
- Biochemically active substances especially low molecular weight substances, have gained increasing importance as analytical species in recent years.
- Short peptide sequences that substitute immunodominant linear epitopes of protein antigens are used as immobilized probes in miniaturized and parallelized immunological analysis techniques.
- immobilized peptides are used for the highly parallel identification of enzyme substrates and inhibitors as well as for the identification of potential protein ligands in drug discovery.
- DNA and RNA probes in a variety of applications is also becoming increasingly important.
- Carbohydrates are used in immobilized form for studies of carbohydrate-mediated molecular processes; small-molecule organic substances from combinatorial chemistry libraries are used in microarray formats for the selection of protein ligands and pharmaceutical agents.
- these molecules can be derived from macromolecules and replace the biochemical function of their lineage molecule.
- Special advantages of low-molecular-weight substances for use in bioanalytics arise from the following circumstances: (i) Unlike macromolecules, eg proteins, many of these substances can be prepared synthetically and particularly economically using established methods. (ii) Low molecular weight substances often turn out to be chemical and physically particularly resistant to external influences. (iii) By synthetic production, the molecules can be defined with unusual or non-natural residues, which in the further course of certain functions, eg in the directed coupling or biochemical activity, take over.
- the coupling of low molecular weight substances to carriers or immobilizing surfaces, in particular for their use as biological probes, is preferably selective and directed.
- ligands having biological activity eg peptides and carbohydrates
- a high proportion of the functional groups of the ligand usually contributes to its biological activity.
- the undirected coupling of such molecules often leads to a modification of the functional groups and inevitably to influence up to the loss of biological activity.
- Directed coupling via selective mechanisms of rejection avoids this problem: ligand and carrier matrix possess mutually reactive, bioorthogonal linker functions or are synthetically equipped with these, which in the next step can selectively react with each other and lead to stable conjugates or complexes.
- Bioorthogonal refers to functions that are unreactive to the other functions of the (bio) chemical environment. The native functional groups of the biological molecules therefore remain unaffected in such a reaction.
- a related object is to provide a particularly advantageous method for producing such carriers.
- a carrier according to the invention has at least two different selective coupling or linker functions which are not complementary to one another and which can not react with the same coupling partner, a first coupling function being provided for coupling to a ligand, preferably a low molecular weight ligand, and at least one further coupling function different therefrom is provided for binding to an immobilizing surface and / or for crosslinking the carrier with each other.
- the low molecular weight ligands are coupled to a macromolecular support, thereby (i) enlarging the presenting surface, (ii) providing the presenting surface with a spatial structure, and (iii) enhancing the biochemical activity of the ligands.
- This coupling can be carried out freely in solution and with an excess of the ligand, since the other linker functions of the carrier are unreactive towards the ligand's linker function (see above).
- the coupling in solution usually proceeds faster and more efficiently than on the surface and is therefore preferred over the likewise possible process variant of a surface reaction.
- a particular advantage of the carrier according to the invention is based on their crosslinkability to three-dimensional spatial structures.
- This networking can typically be through the Addition of bifunctional or multifunctional crosslinking reagents or by the mixture of two or more different carrier species having complementary coupling functions.
- the crosslinking stabilizes the coupled carriers and forms a three-dimensional network with a very high proportion of ligand molecules.
- surface-bound supports are also involved in the crosslinking.
- matrix is used herein in the sense of a three-dimensional structure having the capacity for biological or biochemical interaction with molecules
- the surface bonding of such a matrix is a less common case but required, for example, in chip technology "Surface" to which the supports according to the invention can be bound, a surface which immobilizes the support bound thereto, ie makes it a constituent of a solid phase.
- the macromolecular carriers according to the invention themselves, also in the form of particles or beads which are solubilized or dispersed / suspended in a liquid phase, do not constitute a surface in this sense.
- the selective couplings according to the invention between ligand and carrier, surface and carrier or between two carrier molecules can be both of covalent and affine nature.
- a non-covalent bond is formed between two members of a specific binding pair.
- Some typical non-limiting examples of these are biotin / avidin, biotin / streptavidin, antibody / antigen, receptor / ligand, lectin / saccharide, DNA / DNA, RNA / RNA, DNA / RNA, etc.
- Other suitable examples are known to those skilled in the art or easily found in the literature.
- a preferred and established system for affine coupling is biotin-avidin affinity. Avidin and its bacterial analogs (e.g., streptavidin) highly specifically bind biotin via hydrogen bonding. The stability of the bond comes very close to a covalent coupling.
- the coupling may be due to a covalent bond between a specific reactive group on the support and a reactive group reactive therewith on the ligand or surface or other support or crosslinking reagent.
- these covalent coupling reactions are so-called chemoselective ligations.
- chemo-selective ligations highly selective, in vivo compatible covalent chemical reactions are called.
- molecules for example biomolecules
- linker functions conjugated.
- the reactivity of the groups is orthogonal to the reactivity of other functional groups in the coupling molecules or other molecules in the environment.
- the chemoselective ligation therefore also allows the directed covalent coupling of unprotected low molecular weight substances to carrier matrices in aqueous solvents and under physiological conditions.
- Some non-limiting examples of types of reactions that can be used herein are the reaction between an amino function or sulfhydryl function and a preferably activated carboxy function, the reaction of hydrazides or hydrazines with electrophilic groups, eg, carbonyls or epoxides (see Mahal et al., 1997, Science, 276, 1125-1128), the reaction of electrophilic groups, eg, carbonyls, with aminooxy groups, thiosemicarbazides or beta-aminothiols or thiocarboxylates with alpha-halogeno-carbonyls, or Staudinger ligation (Nilsson et al , 2000, Org Lett, 2, 1939-1941) or a 1,3-dipolar cycloaddition of azides and alkynes (KoIb et al., 2001, Angew Chem, 113, 2056-2075).
- Other suitable reactions can easily be determined by a person skilled
- Either natural functions of the intended coupling partners can be used as coupling functions, or these coupling partners (surface, supports, ligands) are provided with suitable functions via standard linkers using standard conjugation methods (compare FIGS. 2A and 2B).
- Such linkers will generally be bifunctional, with one functional group of the linker being able to react with a functional group of the coupling partner to be modified, and the second functional group providing the desired coupling function.
- Some non-limiting examples are the modification of a carrier or ligand with a biotin group and the directed coupling to a coupling partner with an avidin moiety and / or the introduction of a hydrazide moiety for coupling with eg an aldehyde moiety.
- Natural coupling functions can only be used if the required selectivity, ie exclusive reactivity with the intended coupling partner, is given.
- Low molecular weight ligands will typically have only one coupling or linker function, while the carriers will be provided with a plurality of each linker function.
- the supports according to the invention are crosslinked to three-dimensional spatial structures.
- This crosslinking can be achieved by the addition of bifunctional or multifunctional crosslinking reagents or by the mixture of two or more different carrier species are initiated with complementary coupling functions.
- the crosslinking stabilizes the coupled carriers and forms a three-dimensional network with a very high proportion of ligand molecules.
- surface-bound supports are also involved in the crosslinking.
- crosslinking reagents may be homofunctional if the same linker functions are to be linked together, or heterofunctional if the linker functions differ in their reactivity.
- Suitable crosslinking reagents are known in the art and are commercially available. Some non-limiting examples are glutaraldehyde and other bis-aldehydes, as well as bis-epoxides and bis-NHS esters. Determination of other suitable reagents depending on the given coupling functions is within the skill and knowledge of one of ordinary skill in the art.
- the same coupling function that was used for binding the carriers to an immobilizing surface or a further independent coupling function can be used.
- a coupling function should be used which is different from the coupling function used for the coupling of the ligands.
- the crosslinking takes place in situ, ie for example in the course of a process for Examination of an analyte, eg a low-molecular substance.
- analyte eg a low-molecular substance.
- Suitable carriers according to the invention are all multifunctional and preferably crosslinkable molecules which are large enough to act as carriers.
- Typical non-limiting examples thereof are proteins, polysaccharides or other organic or inorganic polymers.
- Suitable polymers include, for example, polyalkylene glycols, e.g. Polyethylene glycol, polylactic acid, polyalginate, polyglycolic acid, polyalkylenimines, e.g. Polyethyleneimine, poly-L-lysine, polysaccharides, e.g. Cellulose, dextran, polysilanes, polysiloxanes, polyphosphates, latex, poly (meth) acrylates, polystyrene and other plastics.
- the carriers are often employed in the form of particles, particularly nanoparticles (e.g., of latex or coagulated proteins), or beads (e.g., of latex, chitosan, polystyrene, or other suitable polymer).
- the carriers may additionally contain a detectable moiety, for example a fluorescent label, enzyme label or radioactive label.
- a detectable moiety for example a fluorescent label, enzyme label or radioactive label.
- particles or beads may contain a magnetic or paramagnetic component.
- the carrier molecule will occupy at least about four times the volume of the ligand, so that a significant enlargement of the ligand-presenting surface occurs. Due to the invention however, the desired surface enlargement can also be effected indirectly by crosslinking, so that even smaller size ratios are possible in which the carrier essentially only takes over the function of a connecting component in the spatial network.
- Suitable ligands for the carriers according to the invention are in principle molecules of all substance classes which have the required coupling function or can be provided with it. Some non-limiting examples of these are proteins, peptides, nucleic acids, carbohydrates, steroids or other organic or inorganic substances.
- the low molecular weight substances may, for example, be organic substances from a combinatorial chemical library or peptides from a peptide library.
- the ligands are biologically / biochemically active molecules that can exert a biological and / or biochemical function in vivo or in vitro.
- a main field of application of the carriers according to the invention is analytics, in particular bioanalytics.
- methods of analysis in which these carriers can be used for example, all methods of the state of the art are suitable in which investigated analytes or probes are coupled as ligands to carriers or immobilized on surfaces. These are preferably processes in which low molecular weight ligands are used.
- analyte refers to the target molecule of the analytical procedure, the counterpart of which is the probe, so that the low molecular weight ligands can function as probes when used to detect specific target molecules (eg, antibodies) in a complex analysis solution (eg, serum)
- target molecules eg, antibodies
- a complex analysis solution eg, serum
- the ligands may also be the analyte itself if, for example, among a large number of immobilized ligands one is to be found which is to bind to a specific protein (eg a receptor, keyword active substance screening).
- suitable typical analytical methods are nucleic acid assays, protein assays, immunoassays, enzymatic assays, receptor binding assays, ELISA assays, RIA assays, electrophoretic and chromatographic assays, including HPLC, Northern blots, Southern blots, Western blots, colorimetric assays , microscopic and spectroscopic detection methods, assays using biochip or microarray technology or use of beads.
- Figure 1 demonstrates the principle of directed coupling of different coupling partners via selective reaction mechanisms, but without crosslinking.
- Ligand and coupling partner here a surface
- Fig. 2 is a schematic representation of the supports of the invention and their use for the in situ preparation of a three-dimensional network of low molecular weight Ligands and carriers partially immobilized on a surface.
- Figure 2A A support is equipped with two oppositely-reactive, bioorthogonal linker functions (L-IA, L-2A).
- Figure 2B A low molecular weight ligand to be coupled is provided with a linker which forms the complementary reactant to one of the linker functions of the support (L-IB).
- FIG. 2C The ligands are coupled in a reaction to the supports, where the coupling proceeds selectively via the complementary linker functions of one of the bioorthogonal reactions (L-IA and L-IB).
- FIG. 2D The conjugates of carrier and ligand are applied to an immobilizing surface and the conjugates are bound to the surface via the second linker function of the carrier (L-2A) to which the surface has the complementary reaction partner (L-2B).
- Fig. 3 Schematic flow of the concept study described in Example 1.
- Streptavidin is modified by EDC activation with hydrazide functions, which, in addition to biotin affinity, represent the second selective coupling function.
- Biotinylated peptide ligands are coupled in a liquid phase reaction directed to streptavidin and the Reaction mixtures printed directly on aldehyde surfaces.
- the peptide streptavidin complexes are bound to the surface via the hydrazide functions.
- three-dimensional conjugates of surface-bound SAHz and SAHz are generated in the liquid phase by addition of the homobifunctional crosslinker glutaraldehyde.
- the fluorescence images show an exemplary detail of the peptide microarray after the antibody analysis in false color representation.
- the left image shows the fluorescence intensity in the Cy3 channel (laser power 10%, gain 400) and corresponds to the bound protein amount on the surface.
- the right image shows the fluorescence intensity in the Cy5 channel (laser power 20%, gain 400) and corresponds to the amount of bound antibodies from the analysis solution.
- Fluorescence-labeled streptavidin (2 mg / mL in 100 mM phosphate buffer pH 6.0 + 150 mM NaCl) is modified via EDC activation (32 mg / mL EDC) with adipic dihydrazide (32 mg / mL) (12 h reaction time at +4 0 C) ).
- Streptavidin hydrazide (SAHz) and unmodified streptavidin for control are used for the coupling of three different biotinylated peptide antigens (Pol, HeI, Con, see Table 1).
- the coupling takes place in solution with a 10-fold molar excess of the peptides compared to the amount of SAHz used (12 h, +4 0 C).
- the protein-peptide complexes (0.2 mg / mL in MES buffer pH 4.7) are spatially resolved onto aldehyde preactivated glass slides (Schott Nexterion.) Without further purification step using a piezoelectrically controlled dispensing system (sciFLEX Arrayer, Scienion AG, Berlin, Germany) Slide AL, Schott Nexterion AG, Jena, Germany).
- the crosslinking reagent glutaraldehyde solution is dispensed into each microspot (350 pL, final concentration 0.5% w / v). The slides are incubated overnight and then washed and blocked.
- the monoclonal anti-peptide antibodies (Pol mAb, Hel-mAb and Con-mAb, each 1 ⁇ g / ml in PBS, pH 7.4) on the printed surfaces of the slides (2 h, room temperature).
- the slides are washed and then incubated with fluorescently labeled secondary antibody (Cy5 anti-mouse goat antibody, 10 ⁇ g / ml in PBS, pH 7.4, 1 h, room temperature). After rinsing again, the slides are dried and read in the fluorescence scanner (GenePix Professional 4200A, Molecular Devices Corporation, Sunnyvale, CA, USA).
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- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
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- Hematology (AREA)
- Urology & Nephrology (AREA)
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- Medicinal Chemistry (AREA)
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- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Peptides Or Proteins (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
La présente invention concerne des supports réticulables multifonction pour des ligands en particulier de faible poids moléculaire, leur utilisation en analytique ainsi qu'un procédé de production et de réticulation desdits supports. Les supports selon l'invention présentent au moins deux fonctions de couplage sélectif non complémentaires différentes qui ne peuvent pas réagir avec le même partenaire de couplage, une fonction de couplage étant prévue pour le couplage à un ligand, de préférence un ligand de faible poids moléculaire, et au moins une autre fonction de couplage différente étant prévue pour la liaison à une surface immobilisante et/ou la réticulation desdits supports. Cette invention concerne également les structures tridimensionnelles produites par réticulation de ces supports. Selon un mode de réalisation particulier de ladite invention, au moins une partie des supports réticulés ou réticulables est également liée à une surface immobilisante.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE102006003603.4 | 2006-01-25 | ||
DE200610003603 DE102006003603B4 (de) | 2006-01-25 | 2006-01-25 | Vernetzbare multifunktionelle Träger für (niedermolekulare) Liganden und deren Anwendung in der Analytik sowie Verfahren zu deren Herstellung und Vernetzung |
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WO2007085403A2 true WO2007085403A2 (fr) | 2007-08-02 |
WO2007085403A3 WO2007085403A3 (fr) | 2008-02-28 |
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PCT/EP2007/000519 WO2007085403A2 (fr) | 2006-01-25 | 2007-01-22 | Supports réticulables multifonction pour ligands (de faible poids moléculaire), leur utilisation en analytique et procédé de production et de réticulation desdits supports |
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DE (1) | DE102006003603B4 (fr) |
WO (1) | WO2007085403A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111398601A (zh) * | 2014-02-27 | 2020-07-10 | 希森美康株式会社 | 含糖链目标物质的检测方法和试剂、检测用载体及其制造方法 |
CN115356477A (zh) * | 2022-10-20 | 2022-11-18 | 苏州纳微生命科技有限公司 | 一种链霉亲和素磁珠及其制备方法和应用 |
Families Citing this family (1)
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DE102008010692A1 (de) * | 2008-02-22 | 2009-08-27 | Qiagen Gmbh | Neue Matrices, Verfahren zu ihrer Herstellung und ihre Verwendung in Verfahren zur Isolierung von Biomolekülen |
Citations (4)
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US5900481A (en) * | 1996-11-06 | 1999-05-04 | Sequenom, Inc. | Bead linkers for immobilizing nucleic acids to solid supports |
WO2000028088A1 (fr) * | 1998-11-10 | 2000-05-18 | Biocrystal Limited | Nanocristaux comportant des brins de polynucleotides et leur utilisation pour former des dendrimeres dans un systeme d'amplification de signaux |
EP1215485A1 (fr) * | 2000-12-12 | 2002-06-19 | Sony International (Europe) GmbH | Capteurs chimiques sélectifs à base d'ensembles de nanoparticules interconnectées |
US20030162215A1 (en) * | 2002-02-27 | 2003-08-28 | Hitachi Software Engineering Co., Ltd. | Method for detecting biopolymers |
Family Cites Families (3)
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IL132966A0 (en) * | 1998-12-01 | 2001-03-19 | Yissum Res Dev Co | Method and system for detecting oligonucleotides in a sample |
AU2001247697B2 (en) * | 2000-03-22 | 2006-06-22 | Solulink, Incorporated | Hydrazine-based and carbonyl-based bifunctional crosslinking reagents |
JP2007525970A (ja) * | 2003-06-27 | 2007-09-13 | ナノスフェアー インコーポレイテッド | バイオバーコードに基づく標的分析物の検出 |
-
2006
- 2006-01-25 DE DE200610003603 patent/DE102006003603B4/de not_active Expired - Fee Related
-
2007
- 2007-01-22 WO PCT/EP2007/000519 patent/WO2007085403A2/fr active Application Filing
Patent Citations (4)
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US5900481A (en) * | 1996-11-06 | 1999-05-04 | Sequenom, Inc. | Bead linkers for immobilizing nucleic acids to solid supports |
WO2000028088A1 (fr) * | 1998-11-10 | 2000-05-18 | Biocrystal Limited | Nanocristaux comportant des brins de polynucleotides et leur utilisation pour former des dendrimeres dans un systeme d'amplification de signaux |
EP1215485A1 (fr) * | 2000-12-12 | 2002-06-19 | Sony International (Europe) GmbH | Capteurs chimiques sélectifs à base d'ensembles de nanoparticules interconnectées |
US20030162215A1 (en) * | 2002-02-27 | 2003-08-28 | Hitachi Software Engineering Co., Ltd. | Method for detecting biopolymers |
Non-Patent Citations (2)
Title |
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ANDRESEN ET AL: "Peptide microarrays with site-specifically immobilized synthetic peptides for antibody diagnostics" SENSORS AND ACTUATORS B, ELSEVIER SEQUOIA S.A., LAUSANNE, CH, Bd. 113, Nr. 2, 18. Mai 2005 (2005-05-18), Seiten 655-663, XP005279071 ISSN: 0925-4005 * |
FALSEY J R ET AL: "PEPTIDE AND SMALL MOLECULE MICROARRAY FOR HIGH THROUGHPUT CELL ADHESION AND FUNCTIONAL ASSAYS" BIOCONJUGATE CHEMISTRY, ACS, WASHINGTON, DC, US, Bd. 12, Nr. 3, Mai 2001 (2001-05), Seiten 346-353, XP001145929 ISSN: 1043-1802 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111398601A (zh) * | 2014-02-27 | 2020-07-10 | 希森美康株式会社 | 含糖链目标物质的检测方法和试剂、检测用载体及其制造方法 |
CN115356477A (zh) * | 2022-10-20 | 2022-11-18 | 苏州纳微生命科技有限公司 | 一种链霉亲和素磁珠及其制备方法和应用 |
CN115356477B (zh) * | 2022-10-20 | 2023-02-10 | 苏州纳微生命科技有限公司 | 一种链霉亲和素磁珠及其制备方法和应用 |
Also Published As
Publication number | Publication date |
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DE102006003603A1 (de) | 2007-08-02 |
DE102006003603B4 (de) | 2010-02-04 |
WO2007085403A3 (fr) | 2008-02-28 |
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