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US 2024/0262867 A1Published application
Hybrid cyclic libraries and screens thereof
AssigneeThe Johns Hopkins University
InventorsJun O. Liu, Jingxin Wang, Zufeng Guo, Wei Li, Shridhar Bhat, Manisha Das
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Abstract
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.
Claims20
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.
1 more element
A method of identifying a macrocyclic compound comprising:
- (a) contacting the macrocyclic compound with a target protein in the presence of an immunophilin, wherein the macrocyclic compound comprises 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 polypeptide, and a linker moiety;
- (b) detecting the presence of a ternary complex comprising the macrocyclic compound, the immunophilin, and the target protein;
- thereby identifying the macrocyclic compound.
A method of determining the function a protein comprising:
- (a) contacting a library of macrocyclic compounds with the protein encoded by genes in a genome in the presence of an immunophilin, wherein the macrocyclic compound comprises 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 polypeptide, and a linker moiety;
- (b) detecting the presence of a ternary complex comprising the macrocyclic compound, the immunophilin and the protein;
- (c) identifying the protein in the ternary complex;
- and
- (d) determining the function of the protein based on a perturbed chemical and/or cellular function.
2 more elements
Dependencies are inferred from the claim text.