Hybrid cyclic libraries and screens thereof
Provided are novel types of hybrid cyclic libraries that contain a known protein binding domain of a natural product. Also provided are synthetic methods to make such libraries and methods for the deconvolution of hits using partially split-pooled library compounds. Such methods are applicable for use with the entire human proteome to screen such libraries that bind and for the identification of hits.
1. A macrocyclic compound comprising:
an immunophilin-binding domain selected from the group consisting of a FK506-binding protein (FKBP)-binding domain (FKBD) and a cyclosporin-binding cyclophilins (CyP)-binding domain;
an effector domain comprising a heteroatom configured to bind a target protein; and
a linker moiety connecting the immunophilin-binding domain and the effector domain.
2. The macrocyclic compound of claim 1 , wherein the immunophilin-binding domain is an FKBP-binding domain (FKBD).
3. The macrocyclic compound of claim 1 , wherein the immunophilin-binding domain is a CyP-binding domain.
4. The macrocyclic compound of claim 1 , wherein the heteroatom is nitrogen.
5. The macrocyclic compound of claim 1 , wherein the effector domain comprises a polypeptide.
6. The macrocyclic compound of claim 5 , wherein the effector domain comprises a tetrapeptide.
7. The macrocyclic compound of claim 1 , comprising two linker moieties, thereby making the macrocyclic compound with a cyclic sequence of the immunophilin-binding domain, a first linker moiety, the effector domain, and a second linker moiety.
8. The macrocyclic compound of claim 1 , wherein the target protein is calcineurin or target of rapamycin (TOR).
9. The macrocyclic compound of claim 8 , wherein binding with the target protein leads to inhibition of T cell activation and/or tumor cell growth.
10. A pharmaceutical composition comprising the macrocyclic compound of claim 1 and a pharmaceutically acceptable carrier.