Conformationally constrained labeled peptides for imaging and therapy
OwnerMichelle A Schmidt, Jack L Erion +1inventors
InventorsMichelle A Schmidt, Jack L Erion, Ananthachari Srinivasan
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Abstract
Conformational constraints in diagnostic and therapeutic agents in peptides have been introduced by utilization of disulfide bonds and amide cyclizations. These constraints are responsible for altering the stability and specificity of these receptor-targeted agents. Conformationally constrained peptides containing secondary and primary amines, ethers, thioethers, amidines, esters and other functionalities have been synthesized. Methods are disclosed which incorporate multiple features of the above functionalities in the macrocyclic ring of the peptides.
Claims26
A peptide of formula
- 20
- wherein
- AA, AA2, AA3 are natural or unnatural amino acids comprising α-, β- and γ-aminoacids and L- and D-aminoacids;
- a, b=0-10;
- k, l=0-5;
- m=0-20;
- n, n′=1-10;
- P is none, O, S, COO, NH—CO, NR, N—CH(═NH)—NH2, NH—CO—NH, NH—COO;
- R is hydrogen or C1-C5 linear or branched chain alkyl groups bearing —OH at any location;
- p, p′, p″=0-10;
- Q is none, O, S, COO, NH—CO, NR, N—CH(═NH)—NH2;
- E is a group of formula COOR4, CH2OR5, CON(R6)OH or CON(R7)(R8) wherein
- R4 is hydrogen or C1-C5 linear or branched chain alkyl groups,
- R5 is hydrogen or physiologically acceptable, physiologically hydrolyzable ester,
- R6 is hydrogen or C1-C5 linear or branched chain alkyl groups,
- R7, R8 is hydrogen or C1-C5 linear or branched chain alkyl groups or taken together form a cyclic alkyl group C3-C10;
- and
- R9 is H, a dye, a therapeutic agent, a chelating moiety or a metal binding site.
A peptide of formula
- 22
- wherein
- AA, AA2, AA3 are natural or unnatural amino acids comprising α-, β- or γ-aminoacids, and L- or D-aminoacids;
- a, b=0-10;
- k, l=0-5;
- m=0-20;
- n, n′=1-10;
- P is none, O, S, COO, NH—CO, NR, N—CH(═NH)—NH2, NH—CO—NH, NH—COO;
- R is hydrogen or C1-C5 linear or branched chain alkyl groups bearing —OH at any location;
- p, p′, p″=0-10;
- E is a group of formula COOR4, CH2OR5, CON(R6)OH or CON(R7)(R8) wherein
- R4 is hydrogen or C1-C5 linear or branched chain alkyl groups,
- R5 is hydrogen or physiologically acceptable, physiologically hydrolyzable ester,
- R6 is hydrogen or C1-C5 linear or branched chain alkyl groups,
- R7, R8 is hydrogen or C1-C5 linear or branched chain alkyl groups or taken together form a cyclic alkyl group C3-C10;
- and
- R9 is H, a dye, a therapeutic agent, a chelating moiety or a metal binding site.
A peptide of formula
- 24
- wherein
- AA, AA2, AA3 are natural and unnatural amino acids comprising α-, β- or γ-aminoacids and L- and D-aminoacids;
- a, b=0-10;
- k, l=0-5;
- m=0-20;
- n, n′=1-10;
- P, Q is none, O, S, COO, NH—CO, NR, N—CH(═NH)—NH2, NH—CO—NH, NH—COO;
- R is hydrogen or C1-C5 linear or branched chain alkyl groups bearing —OH at any location;
- p, p′=0-10;
- E is a group of formula COOR4, CH2OR5, CON(R6)OH or CON(R7)(R8) wherein
- R4 is hydrogen or C1-C5 linear or branched chain alkyl groups,
- R5 is hydrogen or physiologically acceptable, physiologically hydrolyzable ester,
- R6 is hydrogen or C1-C5 linear or branched chain alkyl groups,
- R7, R8 is hydrogen or C1-C5 linear or branched chain alkyl groups or taken together form a cyclic alkyl group C3-C10;
- and
- R9 is H, a dye, a therapeutic agent, a chelating moiety or a metal binding site.
A method for labeling a peptide with a dye, a therapeutic agent, a chelating moiety or a metal binding site to create a labeled peptide, said method comprising:
- a) synthesizing a macrocyclic ring on said peptide wherein said ring comprises a functional group to which said dye, therapeutic agent, chelating moiety or metal binding site can be attached;
- and
- b) attaching said dye, therapeutic agent, chelating moiety or metal binding site to said peptide.
Dependencies are inferred from the claim text.