Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins

Zhang, Jinpeng; Wang, Xia; Huang, Qingjun; Ye, Jinsong; Wang, Jie

2024-05-31

10.1021/jacs.4c03974

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   影响因子和分区

0002-7863

1520-5126

Genetically encoding a proximal reactive warhead into the protein binder/drug has emerged as an efficient strategy for covalently binding to protein targets, enabling broad applications. To expand the reactivity scope for targeting the diverse natural residues under physiological conditions, the development of a genetically encoded reactive warhead with excellent stability and broad reactivity is highly desired. Herein, we reported the genetic encoding of epoxide-containing tyrosine (EPOY) for developing covalent protein drugs. Our study demonstrates that EPOY, when incorporated into a nanobody (KN035), can cross-link with different side chains (mutations) at the same position of PD-L1 protein. Significantly, a single genetically encoded reactive warhead that is capable of covalent and site-specific targeting to 10 different nucleophilic residues was achieved for the first time. This would largely expand the scope of covalent warhead and inspire the development of covalent warheads for both small-molecule drugs and protein drugs. Furthermore, we incorporate the EPOY into a designed ankyrin repeat protein (Darpin(K13)) to create the covalent binders of KRAS. This covalent KRAS binder holds the potential to achieve pan-covalent targeting of KRAS based on the structural similarity among all oncogenic KRAS mutants while avoiding off-target binding to NRAS/HRAS through a covalent interaction with KRAS-specific residues (H95 and E107). We envision that covalently targeting to H95 will be a promising strategy for the development of covalent pan-KRAS inhibitors in the future.

SCI ; EI

英语

第一 ; 通讯

ChomiX Biotech["2021YFA0910800","2023YFA1506500"] ; National Key Research and Development Program of China["22077059","22277048","92253304"] ; National Natural Science Foundation of China[YESS20200010] ; Young Elite Scientists Sponsorship Program from the China Association for Science and Technology[BNLMS202012] ; Beijing National Laboratory for Molecular Sciences["JCYJ20210324104210028","RCYX20210609103118010","KQTD20221101093558015"] ; Shenzhen Innovation of Science and Technology Commission[A2303067]

Chemistry

Chemistry, Multidisciplinary

WOS:001237252800001

AMER CHEMICAL SOC

Web of Science

Southern Univ Sci & Technol, Coll Sci, Res Ctr Chem Biol & Omics Anal, Dept Chem,Guangdong Prov Key Lab Catalysis, Shenzhen 518055, Peoples R China

Zhang, Jinpeng,Wang, Xia,Huang, Qingjun,et al. Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2024,146(23).

Zhang, Jinpeng,Wang, Xia,Huang, Qingjun,Ye, Jinsong,&Wang, Jie.(2024).Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,146(23).

Zhang, Jinpeng,et al."Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 146.23(2024).