Libraries of oligomers labeled with different tags
First Claim
1. A method of making a set of labelled compounds, by the use of a support and a set of labels, said method comprising the steps of:
- a) at least one first or intermediate step comprising dividing the support into lots, performing a different chemical reaction on each lot of the support so as either to modify that lot of the support or to couple a chemical moiety to that lot of the support, tagging a fraction of each lot of the support with a different label, and combining the said lots of the support, and b) at least one intermediate or final step comprising dividing the support into lots, performing a different chemical reaction on each lot of the support, so as either to modify that lot of the support or to couple a chemical moiety to that lot of the support, tagging a fraction of each lot of the support with a different cleavable label, whereby each different cleavable label is linked to a chemical moiety coupled to the support in a different step and forms with that chemical moiety a labelled compound which is separable from the support, and combining the said lots of the support.
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Abstract
A method of making a set of labelled compounds by the use of a preferably particulate support, comprises dividing the support into lots, performing a different chemical reaction on each lot of the support, e.g. to couple a chemical moiety to that lot of the support, tagging a fraction of each lot of the support with a different label, and combining the said lots of the support. The steps are repeated several times, preferably to build up oligomer molecules carrying labels which identify the nature and position of a monomer unit of the oligomer, and which are releasable from the support. Preferred labels, which are releasable from the compounds by cleavage to provide charged groups for analysis by mass spectrometry, are groups of the trityl (trimethylphenyl) family. Also claimed are libraries of these labels is and their use in assays and nucleic acid analysis methods.
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Citations
74 Claims
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1. A method of making a set of labelled compounds, by the use of a support and a set of labels, said method comprising the steps of:
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a) at least one first or intermediate step comprising dividing the support into lots, performing a different chemical reaction on each lot of the support so as either to modify that lot of the support or to couple a chemical moiety to that lot of the support, tagging a fraction of each lot of the support with a different label, and combining the said lots of the support, and b) at least one intermediate or final step comprising dividing the support into lots, performing a different chemical reaction on each lot of the support, so as either to modify that lot of the support or to couple a chemical moiety to that lot of the support, tagging a fraction of each lot of the support with a different cleavable label, whereby each different cleavable label is linked to a chemical moiety coupled to the support in a different step and forms with that chemical moiety a labelled compound which is separable from the support, and combining the said lots of the support. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 42, 59, 66)
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- 15. A set of labelled compounds wherein a molecule of a compound of the set is tagged with a single label which identifies the nature and/or the position of a component of that molecule, and different molecules of the same compound are tagged with different labels.
- 24. A reagent comprising a solid support which carries on its surface molecules of an oligomer, with different oligomer molecules having the same sequence wherein the oligomer molecules include some shorter oligomer molecules and a shorter oligomer molecule carries a label which identifies the nature and position of a monomer unit of the oligomer molecule.
- 31. A method, which method comprises providing a labelled oligonucleotide or nucleic acid, and removing the label by cleavage to give a charged species which is subjected to mass spectrometry.
- 33. An assay method in which a labelled probe is partitioned into two fractions one of which is determined, the probe comprising a ligand joined to a label by a link which is cleavable to give a charged species for mass spectrometry.
- 37. A library of probes each comprising a ligand joined to a label by a link which is cleavable to give a charged species for analysis by mass spectrometry, wherein each different probe has a different label.
- 41. A compound of formula R1R2R3CY, where Y is a leaving group for reaction with a nucleophilic species, and R1, R2 and R3 are the same or, different and each is a monocyclic or fused ring aromatic group, at least one of which carries a substituent selected from C1-C20 alkoxy or hydrocarbyl either unsubstituted or substituted by carboxylic acid, sulphonic acid, nitro, cyano, hydroxyl, thiol, primary, secondary or tertiary amino, primary or secondary amido, anhydride, carbonyl halide or active ester, provided that R1, R2 and R3 together carry at least two amide groups and/or at least two N-hydroxysuccinimide ester groups.
- 45. An insert for use as a target for laser desorption ionisation mass spectrometry, which insert has a target surface of glass or of an organic polymer carrying an immobilised compound for analysis.
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51. A kit comprising a mass spectrometer and a supply of inserts, for use as targets for laser desorption mass spectrometry, having target surfaces of glass or of an organic polymer.
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52. A system for analysing nucleic acids comprising:
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a solid support carrying an array of nucleic acids to act as targets for analysis or as probes to capture a target;
oligonucleotide reagents tagged with moieties suitable for analysis by mass spectrometry;
reagents and apparatus for biochemical procedures to allow specific interaction between the tagged oligonucleotides and the target;
a means to introduce the samples into a mass spectrometer;
a mass spectrometer.
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53. A system for analysing nucleic acids on a solid support comprising:
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a solid support carrying an array of nucleic acids to act as targets for analysis or as probes to capture a target;
oligonucleotide reagents, tagged with moieties suitable for analysis by mass spectrometry;
reagents and apparatus for biochemical procedures to allow specific interaction between the tagged oligonucleotides and the target carried out on the solid support surface;
a means to introduce the solid support into a mass spectrometer;
a mass spectrometer.
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54. An automated system for analysing nucleic acids comprising:
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oligonucleotide reagents, tagged with moieties suitable for analysis by mass spectrometry;
a mass spectrometer;
a computer to carry out the analysis;
software to interpret a mass spectrum.
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55. A nucleotide or oligonucleotide labelled with a tag suitable for analysis by mass spectrometry, said labelled nucleotide or oligonucleotide being suitable for enyzmatic incorporation, wherein the tag is a compound of formula R1R2R3CY, where Y is a leaving group for reaction with a nucleophilic species, and R1, R2 and R3 are the same or different and each is a monocyclic or fused ring aromatic group, at least one of which carries a substituent selected from C1-C20 alkoxy or hydrocarbyl either unsubstituted or substituted by carboxylic acid, sulphonic acid, nitro, cyano, hydroxyl, thiol, primary, secondary or tertiary amino, primary or secondary amido, anhydride, carbonyl halide or active ester.
Specification