Results
Title

Protein‐Targeted Glycan Editing on Living Cells Disrupts KRAS Signaling.

Authors

Li, Yiran; Huo, Fan; Chen, Liusheng; Wang, Haiqi; Wu, Jianzhuang; Zhang, Peiwen; Feng, Nan; Li, Wei; Wang, Lan; Wang, Yichun; Wang, Xiaojian; Yang, Xiaoliang; Lu, Zhiqiang; Mao, Yang; Yan, Chao; Ding, Lin; Ju, Huangxian

Abstract

The frequent mutation of KRAS oncogene in some of the most lethal human cancers has spurred incredible efforts to develop KRAS inhibitors, yet only one covalent inhibitor for the KRASG12C mutant has been approved to date. New venues to interfere with KRAS signaling are desperately needed. Here, we report a "localized oxidation‐coupling" strategy to achieve protein‐specific glycan editing on living cells for disrupting KRAS signaling. This glycan remodeling method exhibits excellent protein and sugar specificity and is applicable to different donor sugars and cell types. Attachment of mannotriose to the terminal galactose/N‐acetyl‐D‐galactosamine epitopes of integrin αvβ3, a membrane receptor upstream of KRAS, blocks its binding to galectin‐3, suppresses the activation of KRAS and downstream effectors, and mitigates KRAS‐driven malignant phenotypes. Our work represents the first successful attempt to interfere with KRAS activity by manipulating membrane receptor glycosylation.

Subjects

RAS oncogenes; ONCOGENES; GALECTINS; INTEGRINS; EPITOPES; PHENOTYPES; GLYCANS; GALACTOSE

Publication

Angewandte Chemie, 2023, Vol 135, Issue 26, p1

ISSN

0044-8249

Publication type

Academic Journal

DOI

10.1002/ange.202218148