Methods for ligand discovery
First Claim
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1. A method comprising a) contacting a target that comprises a chemically reactive group at or near a site of interest with a compound that is capable of forming a covalent bond with the chemically reactive group;
- b) forming a covalent bond between the target and the compound thereby forming a target-compound conjugate; and
, c) identifying the target-compound conjugate by subjecting the target-compound conjugate to mass spectrometry.
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Abstract
The present invention provides novel methods for ligand discovery. The inventive methods rely on a process termed “tethering” where potential ligands are covalently bonded or “tethered” to a target and subsequently identified.
12 Citations
31 Claims
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1. A method comprising
a) contacting a target that comprises a chemically reactive group at or near a site of interest with a compound that is capable of forming a covalent bond with the chemically reactive group; -
b) forming a covalent bond between the target and the compound thereby forming a target-compound conjugate; and
,c) identifying the target-compound conjugate by subjecting the target-compound conjugate to mass spectrometry.
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2. A mass spectrometer comprising a target-compound conjugate.
- 3. A target-compound conjugate selected from the group consisting of
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8. A method comprising:
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a) contacting a target protein that is capable of forming a disulfide bond with a ligand candidate that is also capable of forming a disulfide bond;
b) forming a disulfide bond between the target protein and the ligand candidate thereby forming a target-ligand conjugate; and
c) identifying the ligand present in the target protein-ligand conjugate. - View Dependent Claims (9, 10, 11, 12, 13, 14, 15, 16, 17)
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18. A library of compounds wherein each member comprises a moiety —
- SSR1 where R1 is unsubstituted C1-C10 aliphatic, substituted C1-C10 aliphatic, unsubstituted aryl, and wherein each member has a different mass.
- View Dependent Claims (19, 20, 21, 22)
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23. A method comprising:
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a) identifying a first compound of the formula RDSSR1 that binds to a target protein;
b) identifying a second compound of the formula RESSR1 that binds to a target protein; and
c) forming a conjugate compound comprising RD and RE wherein RD and RE are each independently C1-C20 unsubstituted aliphatic, C1-C20 substituted aliphatic, unsubstituted aryl, and substituted aryl; and
R1 is unsubstituted C1-C10 aliphatic, substituted C1-C10 aliphatic, unsubstituted aryl. - View Dependent Claims (24, 25)
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26. A method comprising
a) providing a target having an anchoring group that is capable of forming a covalent bond or coordinating a metal at or near a site of interest; -
b) contacting the target with an extender thereby forming a target-extender complex wherein the extender comprises a first functionality that forms either a covalent bond or coordinates a metal and a second functionality that is capable of forming a covalent bond;
c) contacting the target-extender complex with a candidate ligand that comprises a group that is capable of forming a covalent bond with the second functionality;
d) forming a covalent bond between the target-extender complex and the candidate ligand; and
,e) identifying the candidate ligand present in the target-extender-ligand conjugate. - View Dependent Claims (27)
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28. A method comprising:
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a) providing a target having a reactive nucleophile at or near a site of interest;
b) contacting the target with an extender thereby forming a target-extender complex wherein the extender comprises a first functionality that reacts with the nucleophile in the target to form a covalent bond and a second functionality that is capable of forming a disulfide bond;
c) contacting the target-extender complex with a ligand candidate that is capable of forming a disulfide bond;
d) forming a disulfide bond between the target-extender complex and the ligand candidate thereby forming a target-extender-ligand conjugate; and
,e) identifying the ligand candidate present in the target-extender-ligand conjugate. - View Dependent Claims (29, 30, 31)
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Specification