Coferons and methods of making and using them
A monomer useful in prepaπng therapeutic compounds includes a diversity element which potentially binds to a target molecule with a dissociation constant of less than 300 11 M 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 noncovalent 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.
1. A therapeutic multimer comprising:
a plurality of covalently or non-covalently linked monomers, each monomer comprising:
a diversity element which binds to a target molecule with a dissociation constant less than 300 μM; and
a linker element, having a molecular weight less than 500 daltons, and capable of forming a reversible covalent bond or non-covalent tight interaction with a binding partner linker element on another monomer, with a dissociation constant less than 300 μM, with or without a co-factor, under physiological conditions, wherein said diversity element and said linker element are joined together for each monomer directly or indirectly through a connector, the plurality of monomers being reversibly covalently bonded or non-covalently linked together through their linker elements, 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,
wherein said linker element is selected from the group consisting of
where R is an aliphatic or alicyclic group
where Q is an aromatic, heterocyclic or nonheterocyclic ring
where n=0-3, m=1-3 and p =1-2
where
the lines crossed with a dashed line illustrate the one or more bonds formed joining the one or more diversity elements directly or through a connector to the linker element, and
wherein the binding partner linker element is a 1,2-diol, or a 1,3 diol, whereby said linker element and its binding partner linker element, when bound together, form 5 or 6 membered boronate ester rings.
2. The therapeutic multimer of claim 1 , wherein said diversity element binds to the target molecule with a dissociation constant of 100 nM to 100 μM.
3. A therapeutic multimer comprising a plurality of combined therapeutic monomers, each monomer comprising:
a diversity element which binds to a target molecule with a dissociation constant less than 300 μM and
a linker element, having a molecular weight less than 500 daltons, and capable of forming a covalent bond or non-covalent tight interaction with a binding partner linker element on another monomer, with a dissociation constant less than 300 μM, with or without a co-factor, under physiological conditions, wherein said diversity element and said linker element are connected together directly or indirectly through a connector, for each monomer, the plurality of monomers forming the therapeutic multimer, and the diversity elements for the plurality of monomers bind to proximate locations of the target molecule, wherein said linker element is an aromatic, non-heterocyclic compound or an aliphatic compound, selected from the group consisting of the Formula (B1), (B2), (B3), and (B4):
where R is an aliphatic or alicyclic group
where Q is an aromatic, nonheterocyclic ring
where n=0-3, m=1-3, and p=1-2
where
the lines crossed with a dashed line illustrate the one or more bonds formed joining the one or more diversity elements directly or through a connector to the molecule of Formula (B1), (B2), (B3), and (B4), and
wherein the binding partner linker element is a 1,2 diol, or a 1,3 diol, whereby said linker element and its binding partner linker element form 5 or 6 membered boronate ester rings.
4. The plurality of therapeutic monomers of claim 3 , wherein one or more of said diversity elements binds to the target molecule with a dissociation constant of 100 nM to 100 μM.
5. The plurality of therapeutic monomers of claim 3 , wherein one or more of said diversity elements is capable of forming a reversible covalent bond with the target molecule.