title: Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx-Beclin1-mediated autophagic pathway in HBV therapy.
abstract: Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver, functioning as a functional receptor for HBV. Through our continuous efforts to identify NTCP as a novel HBV target, we designed and synthesized a series of new compounds based on the structure of our previous compound NT-5. Molecular docking and MD simulation validated that a new compound named NTI-007 can tightly bind to NTCP, whose efficacy was also measured in vitro virological examination and cytotoxicity studies. Furthermore, autophagy was observed in NTI-007 incubated HepG2.2.15 cells, and results of q-PCR and Western blotting revealed that NTI-007 induced autophagy through NTCP-APOA1-HBx-Beclin1-mediated pathway. Taken together, considering crucial role of NTCP in HBV infection, NTCP-mediated autophagic pathway may provide a promising strategy of HBV therapy and given efficacy of NTI-007 triggering autophagy. Our study suggests pre-clinical potential of this compound as a novel anti-HBV drug candidate.
authors: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors: Jin
authors: J
authors: Zhang
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Lei-Lei
authors: LL
authors: Fu
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Mao
authors: M
authors: Tian
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Hao-Qiu
authors: HQ
authors: Liu
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Jing-Jing
authors: JJ
authors: Li
authors: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors: Yan
authors: Y
authors: Li
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Jun
authors: J
authors: He
authors: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: profhj@163.com.
authors: Jian
authors: J
authors: Huang
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address: ouyangliang@scu.edu.cn.
authors: Liang
authors: L
authors: Ouyang
authors: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors: Hui-Yuan
authors: HY
authors: Gao
authors: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; College of Pharmacy, Xinjiang Medical University, Urumqi 830011, People's Republic of China. Electronic address: profwjh@126.com.
authors: Jin-Hui
authors: JH
authors: Wang
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D045744:Cell Line, Tumor; D006509:Hepatitis B / Q000188:drug therapy*; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects*; D008958:Models, Molecular; D029363:Organic Anion Transporters, Sodium-Dependent / Q000187:drug effects*; D027981:Symporters / Q000187:drug effects*; D015534:Trans-Activators / Q000187:drug effects*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000998:Antiviral Agents; D001055:Apolipoproteins B; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C071908:sodium-bile acid cotransporter
keywords: Anti-HBV drug candidate; Autophagy; Hepatitis B virus (HBV); Sodium taurocholate cotransporting polypeptide (NTCP)