Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions
First Claim
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1. A method of identifying drug non-target biomolecules in a mixture of biomolecules, comprising:
- interacting mixture of biomolecules with a collection of capture compounds, wherein the collection comprises a plurality of capture compounds, comprising sets of capture compounds, wherein each set of capture compounds includes a moiety X that is selected to covalently bind to biomolecules or to bind with sufficiently high affinity so that the resulting complexes of biomolecule/capture compounds are stable under conditions of mass spectrometric analysis;
a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomlecules when the selectivity moiety is present than in its absence; and
a moiety Z for presenting X and Y; and
analyzing the captured biomolecules to identify drug non-targets.
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Abstract
Capture compounds and collections thereof and methods using the compounds for the analysis of biomolecules are provided. In particular, collections, compounds and methods are provided for analyzing complex protein mixtures, such as the proteome. The compounds are multifunctional reagents that provide for the separation and isolation of complex protein mixtures. Automated systems for performing the methods also are provided.
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Citations
168 Claims
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1. A method of identifying drug non-target biomolecules in a mixture of biomolecules, comprising:
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interacting mixture of biomolecules with a collection of capture compounds, wherein the collection comprises a plurality of capture compounds, comprising sets of capture compounds, wherein each set of capture compounds includes a moiety X that is selected to covalently bind to biomolecules or to bind with sufficiently high affinity so that the resulting complexes of biomolecule/capture compounds are stable under conditions of mass spectrometric analysis;
a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomlecules when the selectivity moiety is present than in its absence; and
a moiety Z for presenting X and Y; and
analyzing the captured biomolecules to identify drug non-targets. - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 137, 138, 139, 140, 141, 142)
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2. A method of identifying drug non-target biomolecules in a mixture of biomolecules, comprising:
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interacting mixture of biomolecules with a capture compound, wherein the capture compound includes a moiety X that is selected to covalently bind to biomolecules or to bind with sufficiently high affinity so that the resulting complexes of biomolecule/capture compounds are stable under conditions of mass spectrometric analysis;
a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomlecules when the selectivity moiety is present than in its absence; and
a moiety Z for presenting X and Y; and
analyzing the captured biomolecules to identify drug non-target.
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50. The method of calim 47, wherein the mass modifying tag is a divalent group having the formula X1R10 and is selected from (i)-(vii) as follows:
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(i) X1 is a divalent group selected from O, OC(O)(CH2)yC(O)O, NHC(O), C(O)NH, NHC(O)(CH2)yC(O)O, NHC(S)NH, OP(O-alkyl)O, OSO2O, OC(O)CH2S, S, NH and
andR10 is a divalent group selected from (CH2CH2O)zCH2CH2O, (CH2CH2O)zCH2CH2Oalkylene, alkylene, alkenylene, alkynylene, arylene, heteroarylene, (CH2)zCH2O, (CH2)zCH2Oalkylene, (CH2CH2NH)nCH2CH2NH, CH2CH(OH)CH2O, Si(R12)(R13), CHF and CF2;
where y is an integer from 1 to 20;
z is an integer from 0 to 200;
R11 is the side chain of a naturally occurring á
-amino acid; and
R12 and R12 are each independently selected from alkyl, aryl and aralkyl;
(ii) SS;
(iii) S;
(iv) (N H(CH2)yN HC(O)(CH2)yC(O))zN H(CH2)yN HC(O)—
(CH2)yC(O)O, where y and z are selected as in (i);
(v) (NH(CH2)yC(O))zNH(CH2)yC(O)O, where y and z are selected as in (i);
(vi) (NHCH(R11)C(O))zNHCH(R11)C(O)O, where R11 and z are selected as in (i);
or(vii) (O(CH2)yC(O))nNH(CH2)yC(O)O, where y and z are selected as in (i).
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76. A method of identifying drug non-target biomolecules in a mixture of biomolecules, comprising:
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interacting mixture of biomolecules with a capture compound, wherein the capture compound comprises a moiety X that is selected to covalently bind to biomolecules or to bind with sufficiently high affinity so that the resulting complexes of biomolecule/capture compounds are stable under conditions of mass spectrometric analysis;
a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomlecules when the selectivity moiety is present than in its absence;
a moiety Q, wherein Q permits sorting; and
a moiety Z for presenting X, Y and Q; and
analyzing the captured biomolecules to identify drug non-target. - View Dependent Claims (77, 78, 79, 80)
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81. A collection of capture compounds, comprising a plurality of capture compounds, comprising sets of capture compounds, wherein each set of capture compounds includes a moiety X that is selected to covalently bind to biomolecules or to bind with sufficiently high affinity so that the resulting complexes of biomolecule/capture compounds are stable under conditions of mass spectrometric analysis;
- a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomlecules when the selectivity moiety is present than in its absence; and
a moiety Z for presenting X and Y, wherein the moiety Z is - View Dependent Claims (83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 125, 126, 127, 128, 129, 130, 133, 134, 135, 136)
- a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomlecules when the selectivity moiety is present than in its absence; and
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82. A capture compound selected from
FIG. 23 .
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122. The method of claim 122, wherein step (d) comprises peak integration.
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131. A method of analysis of biomolecules, comprising:
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a) contacting a composition comprising a biomolecule with a collection plurality of capture compounds, comprising sets of capture compounds, wherein each set of capture compounds includes a moiety X that is selected to covalently bind to biomolecules or to bind with sufficiently high affinity so that the resulting complexes of biomolecule/capture compounds are stable under conditions of mass spectrometric analysis;
a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomolecules when the selectivity moiety is present than in its absence;
a moiety Q, such that each set contains a different Q, wherein Q permits separation of each set and a moiety Z for presenting X, Y and Q;
b) digesting the captured biomolecules by chemical or enzymatic treatment;
c) separating each set of captured compounds based on the sorting moiety Q; and
d) analyzing each set of capture compounds to identify the biomolecules.
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132. A method of analysis of biomolecules, comprising:
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a) contacting a composition comprising a biomolecule with a collection capture compounds, wherein each capture compound comprises a moiety X that is selected to covalently bind to biomolecules or to bind with sufficiently high affinity so that the resulting complexes of biomolecule/capture compounds are stable under conditions of mass spectrometric analysis;
a moiety Y that increases the selectivity of the binding by X such that the capture compound binds to fewer biomlecules when the selectivity moiety is present than in its absence;
a moiety Q, wherein Q permits sorting; and
a moiety Z for presenting X, Y and Q;
b) separating each set of captured compounds based on the sorting moiety Q;
c) digesting the captured biomolecules by chemical or enzymatic treatment; and
d) analyzing each set of capture compounds to identify the biomolecules.
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143. A method, comprising:
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contacting a capture compound that comprises a drug with a sample containing biomolecules to effect capture of biomolecules in the sample;
isolating and identifying the captured biomolecules; and
re-designing the drug to eliminate or alter its binding interactions with a captured biomolecule. - View Dependent Claims (144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168)
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Specification