Engineered Cyclic Peptides
An engineered cyclic peptide provides structural constraints to resist non-specific degradation in the human body and includes environment-specific cleavage sites to allow release of a linearized peptide upon reaching a target environment. The linearized peptide can include a reporter molecule or a bioactive therapeutic such that the cyclic peptide is essentially inactive at administration and in circulation but becomes reactive only upon exposure to target-specific environmental factors such as a specific combination of differentially-expressed proteases associated with a target tissue or disease state. The peptides can include tuning that modulate distribution by targeting the particle to specific tissue, bodily fluids, or cell types.
1 . An engineered cyclic peptide comprising:
one or more cleavage sites cleavable within a target environment and generally resistant to cleavage outside a target environment, wherein cleavage of the one or more cleavage sites releases a linearized peptide reactive with the target environment.
2 . The engineered cyclic peptide of claim 1 wherein the target environment is a tumor.
3 . The engineered cyclic peptide of claim 1 wherein the target environment is a biological fluid.
4 . The engineered cyclic peptide of claim 3 wherein the biological fluid is blood.
5 . The engineered cyclic peptide of claim 1 wherein the cleavage site is cleaved by an enzyme present in the target environment.
6 . The engineered cyclic peptide of claim 5 wherein the enzyme is known to be expressed with a certain disease or medical condition.
7 . The engineered cyclic peptide of claim 6 wherein the linearized peptide is a therapeutic peptide operable to treat the disease or medical condition.
8 . The engineered cyclic peptide of claim 1 wherein the linearized peptide is bioactive within the target environment.
9 . The engineered cyclic peptide of claim 1 wherein the linearized peptide is cleavable in response to pH of the target environment.
10 . The engineered cyclic peptide of claim 1 wherein the cyclic peptide is a cyclic depsipeptide and the one or more cleavage sites comprise an ester bond.
11 . The engineered cyclic peptide of claim 1 wherein the cyclic peptide is a macrocyclic peptide.
12 . The engineered cyclic peptide of claim 1 further comprising a carrier.
13 . The engineered cyclic peptide of claim 12 wherein the carrier comprises a poly ethylene glycol (PEG) scaffold of covalently linked PEG subunits.
14 . The engineered cyclic peptide of claim 1 wherein the linearized peptide is a detectable reporter
15 . The engineered cyclic peptide of claim 14 wherein the detectable reporter comprises one selected from the group consisting of: a volatile organic compound; an elemental mass tag; a peptide comprising one or more D-amino acids; a nucleic acid; and a neoantigen.
16 . The engineered cyclic peptide of claim 14 wherein the detectable reporter comprises an elemental mass tag comprising an element of atomic number greater than 20.
17 . The engineered cyclic peptide of claim 14 wherein the reporter comprises an antigen detectable by a hybridization assay.
18 . The engineered cyclic peptide of claim 1 wherein the one or more cleavage sites comprise a plurality of different cleavage sites.
19 . The engineered cyclic peptide of claim 18 wherein the plurality of different cleavage sites are cleaved by different enzymes.
20 . The engineered cyclic peptide of claim 18 wherein cleavage of two or more of the plurality of different cleavage sites is required to release the linearized peptide.
21 . The engineered cyclic peptide of claim 20 wherein the two or more of the plurality of different cleavage sites must be cleaved in a specific order to release the linearized peptide.
22 . The engineered cyclic peptide of claim 21 further comprising a tuning domain that modifies a distribution or residence time of the engineered cyclic peptide within a subject when administered to the subject.
23 . The engineered cyclic peptide of claim 22 further comprising a plurality of tuning domains wherein the tuning domains comprise ligands for receptors of a specific cell or a specific tissue type.
24 . The engineered cyclic peptide of claim 23 wherein the ligands promote accumulation of the engineered cyclic peptide in the specific tissue type or body compartment, wherein the ligands each comprise one selected from the group consisting of a small molecule; a peptide; an antibody; a fragment of an antibody; a nucleic acid; and an aptamer.
25 . The engineered cyclic peptide of claim 22 further comprising a plurality of tuning domains wherein the tuning domains comprise hydrophobic chains that facilitate diffusion of the engineered cyclic peptide across a cell membrane.