2. Academic Validation
  3. Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold

Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold

  • Eur J Med Chem. 2022 Oct 5;240:114608. doi: 10.1016/j.ejmech.2022.114608.
Sheng Han 1,  Heng Li 2,  Weixiong Chen 3,  Li Yang 4,  Xiankun Tong 5,  Jianping Zuo 6,  Youhong Hu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 2 Immunological Disease Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4 Immunological Disease Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 Immunological Disease Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: xktong@simm.ac.cn.
  • 6 Immunological Disease Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: jpzuo@simm.ac.cn.
  • 7 State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China. Electronic address: yhhu@simm.ac.cn.
PMID: 35872393 DOI: 10.1016/j.ejmech.2022.114608
Abstract

Ebola virus (EBOV), one member of the family Filoviridae, can causes hemorrhagic fever and other severe diseases in humans with a high mortality rate (25-90%). Until recently, there were no approved drugs and very limited treatment method for Ebola virus disease. In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of the new chemical scaffold provided more information on the binding modes and the spare volume at the binding cavity, thus can guide the design of the further potent compounds.

Keywords

Ebola virus; Entry inhibitor; Structural optimization.

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