Methods and compositions for controlled polypeptide synthesis
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Abstract
Methods and compositions for the generation of polypeptides having varied material properties are disclosed herein. Methods include means for initiating the polymerization of aminoacid-N-carboxyanhydride (NCA) monomer by combining the monomer with an amido-containing metallacycle, for making self assembling amphiphilic block copolypeptides and related protocols for adding oligo(ethyleneglycol) functionalized aminoacid-N-carboxyanhydrides (NCAs) to polyaminoacid chains. Additional methods include means of adding an end group to the carboxy terminus of a polyaminoacid chain by reacting an alloc-protected amino acid amide with a transition metal-donor ligand complex to forming an amido-amidate metallacycle for use in further polymerization reactions. Novel compositions for use in peptide synthesis and design including five and six membered amido-containing metallacycles and block copolypeptides are also disclosed.
18 Citations
62 Claims
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1-20. -20. (canceled)
- 21. A five membered amido-containing metallacycle comprising a molecule of the general formula:
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22. A six membered amido-containing metallacycle comprising a molecule of the general formula:
- 25. A five membered amido-containing metallacycle comprising a
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29. A method of making an amphiphilic block copolypeptide, comprising the steps of:
- (1) generating a soluble block polypeptide by combining an amount of an oligo (ethyleneglycol) functionalized aminoacid-N-carboxyanhydride (EG-aa-NCA) monomer with an initiator molecule; and
(2) attaching an insoluble block by combining the soluble block with a composition comprising at least one other amino acid NCA monomer. - View Dependent Claims (30)
- (1) generating a soluble block polypeptide by combining an amount of an oligo (ethyleneglycol) functionalized aminoacid-N-carboxyanhydride (EG-aa-NCA) monomer with an initiator molecule; and
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31. The method of 29 wherein the insoluble block contains a mixture of amino acids.
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32. A method of adding an aminoacid-N-carboxyanhydride (NCA) monomer to a soluble block polypeptide, comprising combining the NCA monomer with the soluble block polypeptide, said soluble block having one or more oligo(ethyleneglycol)-functionalized amino acid residues, so that the NCA monomer is added to the polypeptide.
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33. A polypeptide composition comprising a block copolypeptide having:
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(a) a total number of overall monomer units that is greater than about 100 amino acid residues; and (b) a distribution of chain-lengths of at least about 1.01<
Mw/Mn<
1.25. - View Dependent Claims (34, 35, 36, 37, 38, 39)
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- 40. An amphiphilic block copolypeptide comprising a soluble block polypeptide having one or more oligo(ethyleneglycol)-conjugated amino acid residues and an insoluble block comprised substantially of nonionic amino acid residues.
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41. An amphiphilic block copolypeptide comprising:
- (1) a soluble block polypeptide having EG-lysine residues, and (2) an insoluble block polypeptide containing a mixture of two to three different kinds of amino acid components in a statistically random sequence.
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42. An amphiphilic block copolypeptide consisting of at least 3 blocks, wherein one or more of the blocks is a soluble block polypeptide and another block is an insoluble block polypeptide.
- 43. An amphiphilic block copolypeptide comprising a soluble block polypeptide and an insoluble block polypeptide, said soluble block having at least about 30% mole percent identical amino acid residues having charged or oligo(ethyleneglycol)-conjugated side chains and said insoluble block comprising at about 60 to 100 mole percent nonionic amino acid residues.
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48. A chain-end functionalized block polypeptide having ten or more consecutive identical amino acid residues and an endgroup selected from the group consisting of an oligosaccharide, oligonucleotide, fluorescent molecule, polymer chain, small molecule therapeutic, or reactive chemical linker to attach the block copolypeptide to another molecule.
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49. A chain-end functionalized block copolypeptide having an end group selected from the group consisting of a napthyl group, an alkyl group, an allyl group, and cysteinamide.
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50. A polyaminoacid chain comprising at least ten consecutive oligo(ethyleneglycol)-conjugated amino acid residues.
- 54. A method for making EG-functionalized amino acid monomers, comprising the step of combining an ethyleneglycol (EG) derivative with an amino acid having a reactive side group.
- 58. A method of making a soluble block polypeptide comprising the step of combining an amount of an EG functionalized aminoacid-N-carboxyanhydride (NCA) monomer with an initiator molecule comprising a low valent transition metal-Lewis Base ligand complex so that a EG functionalized polyaminoacid chain is generated.
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62. A method of preparing a polypeptide having a defined end group comprising the steps of:
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a) combining an alloc-amino acid amide with an initiator comprising a low valent transition metal-Lewis Base ligand complex for a time and under conditions effective to form an amido-amidate metallacycle; and b) adding one or more amino acid-N-carboxyanhydride monomers to the metallacycle for a time and under conditions effective to form a polypeptide having an end group derived from the alloc-amino acid amide.
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Specification