小分子
细胞生物学
结合
细胞内
内生
化学
微管
癌细胞
诱导剂
细胞
生物物理学
肽
生物
生物化学
癌症
数学分析
遗传学
数学
基因
作者
Xiaofeng Sun,Chengjian Zhou,Simin Xia,Xi Chen
标识
DOI:10.1038/s41467-023-37237-x
摘要
Chemically induced proximity (CIP) is a powerful tool to study cellular functions. However with current CIP inducers it is difficult to directly modulate unligandable and endogenous targets, and therapeutic translational potential is also restricted. Herein, we combine CIP and chemical nanobody engineering and create cell-permeable small molecule-nanobody conjugate inducers of proximity (SNACIPs). The SNACIP inducer cRGT carrying a cyclic cell-penetrating peptide rapidly enters live cells and dimerizes eDHFR and GFP-variants. cRGT enables minute-scale, reversible, no-wash and dose-dependent control of cellular processes including signaling cascade, cargo transport and ferroptosis. Small-molecule motifs can also be installed via post-translational modifications. Therefore, latent-type SNACIPs including cRTC are designed that are functionally assembled inside living cells. cRTC contains a nanobody against an intrinsically disordered protein TPX2, a microtubule nucleation factor overexpressed in various cancers. Cancer cell proliferation is inhibited and tumor growth is suppressed in vivo. Hence, SNACIPs are valuable proximity inducers for regulating cellular functions.
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