Amphiphilic derivatives of thioether containing block copolypeptides
Methods for preparation of novel amphiphilic derivatives of thioether containing block copolypeptides with narrow chain length distributions are described. These block copolymers can be chemically modified by oxidation and alkylation of the thioether containing residues. These materials generate self-assembled micelles, vesicles and hydrogels, or emulsions with oil phases. These assemblies can be used to encapsulate and delivery therapeutic molecules. The assemblies can be taken up by cells to release molecules from the assemblies.
1. A process for preparing an amphiphilic block copolypeptide with oxidized thioether groups comprising:
synthesizing a block copolypeptide wherein at least one of the blocks contains at least 3 consecutive hydrophobic amino acids selected from leucine, phenylalanine, alanine, isoleucine, valine, tyrosine, and tryptophan, and wherein at least one of the blocks contains at least 3 consecutive thioether containing amino acids selected from methionine, S-methyl-cysteine, S-ethyl-cysteine, S-allyl-cysteine, S-benzyl-cysteine, S-farnesyl-cysteine, S-propargyl-cysteine, S-methyl-homocysteine, S-ethyl-homocysteine, S-allyl-homocysteine, S-benzyl-homocysteine, S-farnesyl-homocysteine, and S-propargyl-homocysteine;
adding an oxidizing reagent to the block copolypeptide; and
reacting the block copolypeptide so that the majority of the thioether groups in the polypeptide are oxidized, thereby forming the amphiphilic block copolypeptide with oxidized thioether groups.
2. The process of claim 1 , wherein the thioether containing amino acids are methionine.
3. The process of claim 1 , wherein the thioether containing amino acids are one or more of S-methyl-cysteine, S-ethyl-cysteine, S-allyl-cysteine, S-benzyl-cysteine, S-farnesyl-cysteine, and S-propargyl-cysteine.
4. The process of claim 1 , wherein the thioether containing amino acids are one or more of the following: S-methyl-homocysteine, S-ethyl-homocysteine, S-allyl-homocysteine, S-benzyl-homocysteine, S-farnesyl-homocysteine, and S-propargyl-homocysteine.
5. The process of claim 1 , wherein the oxidized thioether groups in the amphiphilic block copolypeptide are one or more of the following: sulfoxide, and sulfone.
6. The process of claim 1 wherein the hydrophobic amino acids are one or more of L-leucine, L-phenylalanine, L-alanine, L-isoleucine, L-valine, L-tyrosine, and L-tryptophan.
7. The process of claim 1 , wherein the block copolypeptide is a diblock copolypeptide.
8. The process of claim 1 , wherein the block copolypeptide is a triblock copolypeptide.
9. The process of claim 1 , wherein the thioether containing amino acids are L-methionine.
10. The process of claim 1 , wherein the hydrophobic amino acids are L-leucine or L-phenylalanine.
11. The process of claim 1 , wherein the oxidizing reagent comprises H 2 O 2 .
12. The process of claim 1 , wherein the amphiphilic block copolypeptide with oxidized thioether groups is
poly(L-methionine-sulfoxide) 65 -block-poly(L-leucine 0.5 -co-L-phenylalanine 0.5 ) 20 ;
poly(Nε-trifluoroacetyl-L-lysine) 11 -block-poly(L-methionine sulfoxide) 55 -block-poly(L-leucine 0.5 -co-L-phenylalanine 0.5 ) 20 ;
poly(Nε-trifluoroacetyl-L-lysine) 21 -block-poly(L-methionine sulfoxide) 55 -block-poly(L-leucine 0.5 -co-L-phenylalanine 0.5 ) 20 ;
poly(L-lysine) 10 -block-poly(L-methionine sulfoxide) 55 -block-poly(L-leucine 0.5 -co-L-phenylalanine 0.5 ) 20 ;
poly(L-lysine) 20 -block-poly(L-methionine sulfoxide) 55 -block-poly(L-leucine 0.5 -co-L-phenylalanine 0.5 ) 20 ;
poly(L-homoarginine) 10 -block-poly(L-methionine sulfoxide) 55 -block-poly(L-leucine 0.5 -co-L-phenylalanine 0.5 ) 20 ; or
poly(L-homoarginine) 20 -block-poly(L-methionine sulfoxide) 55 -block-poly(L-leucine 0.5 -co-L-phenylalanine 0.5 ) 20 .