Coferons and methods of making and using them
The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes a diversity element which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the diversity element. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to said diversity element, and is capable of forming a reversible covalent bond or non-covalent interaction with a binding partner of the linker element. The monomers can be covalently or non-covalently linked together to form a therapeutic multimer or a precursor thereof. Also disclosed is a method of screening for therapeutic multimer precursors which bind to a target molecule associated with a condition and a method of screening for linker elements capable of binding to one another. The present invention additionally relates to a therapeutic multimer, which includes a plurality of covalently or non-covalently linked monomers, therapeutic monomers, and uses of such dimers and monomers.
1. A therapeutic dimer having:
a boronate ester moiety formed from a phenylboronic acid linker element and a cis-1,2 diol binding partner;
a diversity element joined to the phenylboronic acid linker element through a connector; and
a diversity element joined to the cis-1,2 diol binding partner through another connector, wherein the diversity element joined to the cis-1,2 diol binding partner and the diversity element joined to the phenylboronic acid linker each bind to proximate locations on a target molecule, and wherein said diversity element is a molecule having a structure based on one or more of monocyclic scaffolds, bicyclic scaffolds, tetracyclic scaffolds, spiro scaffolds, or combinations thereof linked by a covalent bond forming multicore scaffolds; and wherein said target molecule is (1) G-protein coupled receptors, (2) nuclear receptors, (3) voltage gated ion channels, (4) ligand gated ion channels, (5) receptor tyrosine kinases, (6) growth factors, (7) proteases, (8) sequence specific proteases, (9) phosphatases, (10) protein kinases, (11) bioactive lipids, (12) cytokines, (13) chemokines, (14) ubiquitin ligases, (15) viral regulators, (16) cell division proteins, (17) scaffold proteins, (18) DNA repair proteins, (19) bacterial ribosomes, (20) histone deacetylases, (21) apoptosis regulators, (22) chaperone proteins, (23) serine/threonine protein kinases, (24) cyclin dependent kinases, (25) growth factor receptors, (26) proteasome, (27) signaling protein complexes, (28) protein/nucleic acid transporters, or (29) viral capsids.
2. The therapeutic dimer of claim 1 , wherein the cis-1,2 diol binding partner is a catechol.
3. A therapeutic multimer comprising:
a monomer having a diversity element and a linker element with an aromatic non-heterocyclic ring containing a boronic acid group, wherein the linker element is joined to the diversity element through a connector;
another monomer having a binding partner linker element having a 1,2 or 1,3 diol, and joined to another diversity element through another connector, wherein
the linker element and the binding partner linker element form a reversibly covalently bonded 5 or 6 membered boronate diester ring; and wherein
each diversity element independently for each occurrence binds to a target molecule with a dissociation constant less than 300 μM, and wherein said diversity element is a molecule having a structure based on one or more of monocyclic scaffolds, bicyclic scaffolds, tetracyclic scaffolds, spiro scaffolds, or combinations thereof linked by a covalent bond forming multicore scaffolds; and wherein said target molecule is (1) G-protein coupled receptors, (2) nuclear receptors, (3) voltage gated ion channels, (4) ligand gated ion channels, (5) receptor tyrosine kinases, (6) growth factors, (7) proteases, (8) sequence specific proteases, (9) phosphatases, (10) protein kinases, (11) bioactive lipids, (12) cytokines, (13) chemokines, (14) ubiquitin ligases, (15) viral regulators, (16) cell division proteins, (17) scaffold proteins, (18) DNA repair proteins, (19) bacterial ribosomes, (20) histone deacetylases, (21) apoptosis regulators, (22) chaperone proteins, (23) serine/threonine protein kinases, (24) cyclin dependent kinases, (25) growth factor receptors, (26) proteasome, (27) signaling protein complexes, (28) protein/nucleic acid transporters, or (29) viral capsids; and
the diversity elements of the therapeutic multimer bind to proximate locations of the target molecule, wherein the therapeutic multimer binds to the target molecule with a dissociation constant of less than 10 μM.
4. The therapeutic multimer of claim 3 , wherein one or more of said diversity elements is capable of forming a reversible covalent bond with the target molecule.
5. The therapeutic multimer of claim 3 , wherein the linker element and the binding partner linker element each has a molecular weight less than 500 daltons.