Chemical synthesis and screening of bicyclic peptide libraries
Disclosed herein are bicyclic peptide compounds, compositions comprising same, methods for making same, and libraries comprising same. The disclosed compounds, in various aspects, are useful for treating a variety of disorders, including inflammatory disorders, autoimmune disorders, and disorders of uncontrolled cellular proliferation. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A compound of Formula I:
wherein:
A is benzene;
p, q, and r are independently selected from 0, 1, and 2;
B 1 , B 2 , and B 3 are independently selected from O and NR 1 ; wherein R 1 is H, or substituted or unsubstituted C 1 -C 5 alkyl;
L 1 is selected from substituted or unsubstituted C 1 -C 6 alkyl, amino acid, and a linker to a solid phase support;
L 2 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, amino acid, and a linker to a solid phase support;
D is selected from substituted or unsubstituted C 1 -C 6 alkyl, or amino acid residue; and
X m and X n independently comprise a sequence of 1-10 amino acids.
2. The compound of claim 1 , wherein one or more of p, q, and r is 1.
3. The compound of claim 1 , wherein L 1 and L 2 are independently selected from an amino acid.
4. The compound of claim 1 , wherein L 1 is lysine.
5. The compound of claim 1 , wherein D is an amino acid residue.
6. The compound of claim 1 , wherein one or more of B 1 , B 2 , and B 3 is NR 1 , and R 1 is H.
7. The compound of claim 1 , wherein each of p, q, and r is 0; L 1 is lysine; each of B 1 , B 2 , and B 3 is NR 1 , wherein R 1 is H; and D-L 2 is —CH 2 —CH(NH)—C(O)—NH—R 0 .
8. The compound of claim 7 , wherein the compound is of Formula I-A:
wherein:
X m and X n are as defined in Formula I;
R 0 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl; and
K has a structure represented by a formula:
9. The compound of claim 1 , wherein X m and X n comprise different amino acid sequences.
10. The compound of claim 1 , wherein X m comprises 3-7 residues.
11. The compound of claim 1 , wherein X m comprises 4-6 residues.
12. The compound of claim 1 , wherein X n comprises 2-6 residues.
13. The compound of claim 1 , wherein X n comprises 3-5 residues.
14. The compound of claim 1 , wherein the compound has a molecular weight of 500-5000.
15. The compound of claim 1 , wherein X m and X n are selected from SEQ ID NO: 1-4 and 6-63.
16. The compound of claim 1 , wherein X m and X n are selected from SEQ ID NO: 1-4 and 6-25.