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

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 () and Zhenhua Shao ()
Additional contact information
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
Wei Yan: Sichuan University
Xiawei Wei: Sichuan University
Zhenhua Shao: Sichuan University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36673-z

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