Small molecule printing

• US 20030215876A1
• Filed: 02/20/2003
• Published: 11/20/2003
• Est. Priority Date: 05/11/1999
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), Howard Hughes Medical Institute
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Schreiber, Stuart L., Koehler, Angela N., Park, Seung Bum, Barnes-Seeman, David
• Granted Patent: US 7,932,213 B2
• Time in Patent Office: Days
• US Class Current: 435/7.1
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00387 Applications using probes
• CPC Class Codes: B01J 2219/00454 by chemical cleavage from the solid support
• CPC Class Codes: B01J 2219/00459 Beads
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00533 essentially rectangular
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C07C 311/49 to nitrogen atoms
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• CPC Class Codes: C40B 40/04 Libraries containing only organic compounds
• CPC Class Codes: C40B 50/14 Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: G01N 33/54353 with ligand attached to the carrier via a chemical coupling agent coatings G01N33/54393
• CPC Class Codes: Y10S 436/809 Multifield plates or multicontainer arrays

Abstract

The present invention provides compositions and methods to facilitate the identification of compounds that are capable of interacting with a biological macromolecule of interest. In one aspect, a composition is provided that comprises an array of one or more types of chemical compounds attached to a solid support, wherein the density of the array of compounds is at least 1000 spots per cm². In particularly preferred embodiments, these compounds are attached to the solid support through a covalent interaction. In general, these inventive arrays are generated by: (1) providing a solid support, wherein said solid support is functionalized with a selected chemical moiety capable of interacting with a desired chemical compound to form an attachment; (2) providing one or more solutions of one or more types of compounds to be attached to the solid support; and (3) delivering said one or more types of compounds to the solid support, whereby an array is formed and the array of compounds has a density of at least 1000 spots per cm². In another aspect, the present invention provides methods for utilizing these arrays to identify small molecule partners for biological macromolecules of interest comprising: (1) providing an array of compounds, wherein the array has a density of at least 1000 spots per cm²; (2) contacting the array with one of more types of biological macromolecules of interest; and (3) determining the interaction of specific small molecule-biological macromolecule partners.

Claims

1. An array comprising:

a plurality of more than one type of chemical compound attached to a solid support through a diazobenzylidene moiety, wherein the density of said array of compounds comprises at least 1000 spots per cm^2.

2. The array of claim 1, wherein said array of chemical compounds comprises an array of small molecules.

3. The array of claim 1, wherein said array of chemical compounds comprises an array of non-oligomeric chemical compounds.

4. The array of claim 1, wherein said array of chemical compounds comprises an array of non-peptidic and non-oligomeric chemical compounds.

5. The array of claim 1, wherein said attachment is characterized in that the benzylidene linkage is robust enough so that the compounds are (1) not inadvertently cleaved during subsequent manipulation steps and (2) inert so that the functionalities employed do not interfere with subsequent manipulation steps.

6. The array of claim 1, wherein each of said chemical compounds in said array is attached to the solid support through a linkage generated by a nucleophilic displacement reaction.

7. The array of claim 1, wherein each of said chemical compounds in said array is attached to the solid support through a linkage generated by a nucleophilic displacement of N₂ by a heteroatom.

8. The array of claim 1, wherein the benzylidene linker attaching compound to glass slide is as shown below:

9. The array of claim 1, wherein the benzylidene linker attaching compound to glass slide is as shown below:

10. The array of claim 1, wherein the benzylidene linker attaching compound to glass slide is as shown below:

11. The array of claim 1, wherein the benzylidene linker attaching compound to glass slide is as shown below:

12. The array of claim 1, wherein the benzylidene linker attaching compound to glass slide is as shown below:

13. The array of claim 1, wherein the solid support is glass.

14. The array of claim 1, wherein the solid support is derivatized glass.

15. The array of claim 1, wherein the solid support is silylated glass.

16. The array of claim 1, wherein the solid support is γ

-aminopropylsilylated glass.

17. The array of claim 1, wherein the solid support is a polymer.

18. The array of claim 1, wherein the solid support is metal.

19. The array of claim 1, wherein the solid support is a metal-coated surface.

20. The array of claim 1, wherein the solid support is a gold-coated surface.

25. A method for forming the array of claim 1, the method comprising:

providing a solid support, wherein said solid support is functionalized with a diazobenzylidene moiety capable of interacting with more than one type of chemical compound to form a covalent linkage;

providing one or more solutions of more than one type of chemical compounds to be attached to the solid support; and

delivering said one or more solutions of said more than one type of chemical compounds to the solid support, whereby each of said chemical compounds is attached to the solid support through a covalent interaction, and whereby said array of compounds has a density of at least 1000 spots per cm².

26. The method of claim 25, wherein said solid support comprises a glass slide.

27. The method of claim 25, wherein providing a solution of one or more types of compounds to be attached to the solid support comprises providing one or more solutions generated from a library of compounds, wherein each member of said library is initially attached to a bead, placed in an individual well, then cleaved from the bead to provide the solution.

30. A method of identifying small molecule partners for biological macromolecules of interest comprising:

providing the array of claim 1, wherein said array comprises an array of small molecules attached to a support through a benzylidene moiety, and wherein said array of small molecules has a density of at least 1000 spots per cm²;

contacting said array with one of more types of biological macromolecules of interest; and

determining the binding of specific small molecule-biological macromolecule partners.

31. A method for identifying small molecule partners for a gene product comprising:

providing the array of claim 1, wherein said array comprises an array of small molecules attached to a support through a benzylidene moiety, and wherein said array of small molecules has a density of at least 1000 spots per cm²

contacting said array with a library of recombinant proteins; and

determining the binding of specific recombinant proteins with small molecule partner

21. An array comprising:

a plurality of one or more types of chemical compounds attached to a glass or polymer support through a benzylidene moiety, wherein the density of said array of compounds comprises at least 1000 spots per cm².

22. The array of claim 21, wherein said array of chemical compounds comprises an array of small molecules.

23. The array of claim 21, wherein said array of chemical compounds comprises an array of non-peptidic and non-oligomeric chemical compounds.

24. The array of claim 21, wherein said attachment is characterized in that the benzylidene linkage is robust enough so that the compounds are (1) not inadvertently cleaved during subsequent manipulation steps and (2) inert so that the functionalities employed do not interfere with subsequent manipulation steps.

28. A method for forming the array of claim 21, the method comprising:

providing a glass or polymeric solid support, wherein said solid support is functionalized with a diazobenzylidene capable of interacting with one or more types of chemical compounds to form a covalent linkage;

providing one or more solutions of said one or more types of compounds to be attached to the glass or polymer solid support; and

delivering said one or more solutions of said one or more types of chemical compounds to the solid support, whereby each of said chemical compounds is attached to the solid support though a covalent interaction, and whereby said array of compounds has a density of at least 1000 spots per cm².

29. The method of claim 28, wherein providing a solution of one or more types of compounds to be attached to the solid support comprises providing one or more solutions generated from a library of compounds, wherein each member of said library is initially attached to a bead, placed in an individual well, then cleaved from the bead to provide the solution.

32. A solid support comprising a solid support derivatized with diazobenzylidene moieties.

33. The solid support of 36 having the structure: