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

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

  • Nat Commun. 2023 Feb 21;14(1):962. doi: 10.1038/s41467-023-36673-z.
Jie Zhao # 1,  Hong Fu # 1,  Jingjing Yu # 1,  Weiqi Hong # 1,  Xiaowen Tian # 1,  Jieyu Qi # 2,  Suyue Sun 1,  Chang Zhao 1,  Chao Wu 1,  Zheng Xu 1,  Lin Cheng 3,  Renjie Chai 4 5 6,  Wei Yan 7,  Xiawei Wei 8,  Zhenhua Shao 9 10
Affiliations

Affiliations

  • 1 Division of Nephrology and Kidney Research Institute, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2 State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
  • 3 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 4 State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China. renjiec@seu.edu.cn.
  • 5 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. renjiec@seu.edu.cn.
  • 6 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. renjiec@seu.edu.cn.
  • 7 Division of Nephrology and Kidney Research Institute, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. weiyan2018@scu.edu.cn.
  • 8 Division of Nephrology and Kidney Research Institute, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. xiaweiwei@scu.edu.cn.
  • 9 Division of Nephrology and Kidney Research Institute, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. zhenhuashao@scu.edu.cn.
  • 10 Department of Nephrology, Hainan General Hospital, Haikou, Hainan, 570311, China. zhenhuashao@scu.edu.cn.
  • # Contributed equally.
PMID: 36810324 DOI: 10.1038/s41467-023-36673-z
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.

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