Supramolecular modification of proteins
The modification of biomolecules, small molecules, and other agents of via conjugation of excipients, tags, or labels is of great importance. For example, the modification of therapeutic agents can confer improved stability, solubility, duration of action, or pharmacological properties. Supramolecular chemistry utilizes specific, directional, reversible, non-covalent molecular recognition motifs in order to achieve organization of molecules, and can be used to complex tags to agents of interest (e.g., insulin, glucagon, antibodies). The present invention provides useful supramolecular complexes wherein an agent of interest is specifically bound to a host via non-covalent interactions, and wherein the host is conjugated to a tag. The present invention also provides methods and compounds useful in preparing supramolecular complexes, and methods of treating diseases using the supramolecular complexes.
1. An agent associated with a tag, wherein:
the agent is directly bound to a macrocyclic host via non-covalent interactions; and
the macrocyclic host is conjugated to the tag; wherein
the agent is a protein or peptide;
the tag is a polymer; and
the macrocyclic host is an optionally substituted cucurbit[7]uril (CB[7]).
2. The agent of claim 1 , wherein the agent is a protein.
3. The agent of claim 2 , wherein the protein is an antibody.
4. The agent of claim 1 , wherein the macrocyclic host is conjugated to the tag via a linker.
5. The agent of claim 4 , wherein the linker is of Formula (L-1):
wherein:
each of L 1 and L 2 is independently a bond, optionally substituted alkylene, or optionally substituted heteroalkylene; and
A is a bond, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
6. The agent of claim 1 , wherein the non-covalent interactions are guest-host interactions.
7. The agent of claim 1 , wherein the agent is a protein, and the macrocyclic host binds an amino acid residue of the protein.
8. The agent of claim 7 , wherein the macrocyclic host binds an amino acid selected from the group consisting of phenylalanine, tryptophan, and tyrosine.
9. A compound comprising an optionally substituted cucurbituril cucurbit[7]uril (CB [7]) conjugated to a tag, or a salt thereof; wherein the tag is a polymer.
10. The compound of claim 9 , wherein the compound is of Formula (CB-1):
CB-L 1 -A-L 2 -TAG
(CB-1),
or a salt thereof, wherein:
CB is an optionally substituted CB [7];
TAG is a polymer;
each of L 1 and L 2 is independently a bond, optionally substituted alkylene, or optionally substituted heteroalkylene; and
A is a bond, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
11. A compound of Formula (CB-2a) or Formula (CB-2b):
or a salt thereof, wherein:
CB is an optionally substituted cucurbituril;
TAG is a tag selected from the group consisting of polymers, therapeutic agents, targeting agents, radionuclides, fluorophores, chromophores, phosphorescent agents, dyes, chemiluminescent agents, particles, colorimetric labels, magnetic labels, haptens, biomolecules, small molecules, fatty acids, hydrocarbon chains, excipients, and diagnostic agents;
each of L 1 and L 2 is independently a bond, optionally substituted alkylene, or optionally substituted heteroalkylene;
Y is CR a or N;
each instance of Ra is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR aa , —SR aa , —N(R aa ) 2 , —NO 2 , or —CN, or two R a attached to adjacent atoms are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
each occurrence of R aa is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R aa attached to the same nitrogen atom are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; and
m is 0 or an integer from 1-10, inclusive.
12. The compound of claim 11 , wherein the compound is of Formula (PEG-T-CB[7]):
or a salt thereof.
13. A pharmaceutical composition comprising an agent of claim 1 , and a pharmaceutically acceptable excipient.
14. The agent of claim 2 , wherein the protein is a therapeutic protein.
15. The agent of claim 2 , wherein the protein is unmodified.
16. The agent of claim 2 , wherein the protein is insulin.
17. The agent of claim 2 , wherein the protein is glucagon.
18. The agent of claim 1 , wherein the polymer is a polyether, polyboronic acid, or polyboronic ester.
19. The agent of claim 1 , wherein the polymer is polyethylene glycol (PEG).
20. The agent of claim 1 , wherein the agent is insulin; and the tag is polyethylene glycol (PEG).
21. The agent of claim 1 , wherein the agent is glucagon; and the tag is polyethylene glycol (PEG).
22. The agent of claim 1 , wherein the agent is glucagon; and the tag is a polyboronic acid or polyboronic ester.
23. The agent of claim 1 , wherein the agent is an antibody; and the tag is polyethylene glycol (PEG).
24. The compound of claim 9 , wherein the polymer is a polyether, polyboronic acid, or polyboronic ester.
25. The compound of claim 9 , wherein the polymer is polyethylene glycol (PEG).
26. The compound of claim 11 , wherein CB is optionally substituted CB[7].
27. The compound of claim 11 , wherein TAG is a polymer.
28. The compound of claim 27 , wherein the polymer is a polyether, polyboronic acid, or polyboronic ester.
29. The compound of claim 28 , wherein the polymer is polyethylene glycol (PEG).
30. The compound of claim 11 , wherein the compound is of Formula (CB-3a) or (CB-3b):
or a pharmaceutically acceptable salt thereof.