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Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine

Author

Listed:
  • Jie Zhao

    (Sichuan University)

  • Hong Fu

    (Sichuan University)

  • Jingjing Yu

    (Sichuan University)

  • Weiqi Hong

    (Sichuan University)

  • Xiaowen Tian

    (Sichuan University)

  • Jieyu Qi

    (Southeast University)

  • Suyue Sun

    (Sichuan University)

  • Chang Zhao

    (Sichuan University)

  • Chao Wu

    (Sichuan University)

  • Zheng Xu

    (Sichuan University)

  • Lin Cheng

    (University of Electronic Science and Technology of China)

  • Renjie Chai

    (Southeast University
    University of Electronic Science and Technology of China
    Nantong University)

  • Wei Yan

    (Sichuan University)

  • Xiawei Wei

    (Sichuan University)

  • Zhenhua Shao

    (Sichuan University
    Hainan General Hospital)

Abstract

Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors.

Suggested Citation

  • Jie Zhao & Hong Fu & Jingjing Yu & Weiqi Hong & Xiaowen Tian & Jieyu Qi & Suyue Sun & Chang Zhao & Chao Wu & Zheng Xu & Lin Cheng & Renjie Chai & Wei Yan & Xiawei Wei & Zhenhua Shao, 2023. "Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36673-z
    DOI: 10.1038/s41467-023-36673-z
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    Cited by:

    1. Xin Chen & Kexin Wang & Jianfang Chen & Chao Wu & Jun Mao & Yuanpeng Song & Yijing Liu & Zhenhua Shao & Xuemei Pu, 2024. "Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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