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Small molecule-nanobody conjugate induced proximity controls intracellular processes and modulates endogenous unligandable targets

Author

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  • Xiaofeng Sun

    (Harbin Institute of Technology (HIT)
    School of Life Science and Technology, HIT)

  • Chengjian Zhou

    (Harbin Institute of Technology (HIT)
    School of Life Science and Technology, HIT)

  • Simin Xia

    (Harbin Institute of Technology (HIT))

  • Xi Chen

    (Harbin Institute of Technology (HIT)
    School of Life Science and Technology, HIT)

Abstract

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.

Suggested Citation

  • Xiaofeng Sun & Chengjian Zhou & Simin Xia & Xi Chen, 2023. "Small molecule-nanobody conjugate induced proximity controls intracellular processes and modulates endogenous unligandable targets," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37237-x
    DOI: 10.1038/s41467-023-37237-x
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