2. Academic Validation
  3. Identification of a clinical compound losmapimod that blocks Lassa virus entry

Identification of a clinical compound losmapimod that blocks Lassa virus entry

  • Antiviral Res. 2019 Jul;167:68-77. doi: 10.1016/j.antiviral.2019.03.014.
Xiaoyu Zhang 1,  Feihu Yan 2,  Ke Tang 1,  Qing Chen 1,  Jiamei Guo 3,  Wenjun Zhu 4,  Shihua He 4,  Logan Banadyga 4,  Xiangguo Qiu 5,  Ying Guo 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada; Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Science, Changchun, China.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 4 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2, Canada.
  • 5 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada. Electronic address: xiangguo.qiu@canada.ca.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: yingguo6@imm.ac.cn.
PMID: 30953674 DOI: 10.1016/j.antiviral.2019.03.014
Abstract

Lassa virus (LASV) causes Lassa hemorrhagic fever in humans and poses a significant threat to public health in West Africa. Current therapeutic treatments for Lassa fever are limited, making the development of novel countermeasures an urgent priority. In this study, we identified losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, from 102 screened compounds as an inhibitor of LASV Infection. Losmapimod exerted its inhibitory effect against LASV after p38 MAPK down-regulation, and, interestingly, had no effect on other arenaviruses capable of causing viral hemorrhagic fever. Mechanistic studies showed that losmapimod inhibited LASV entry by affecting the stable signal peptide (SSP)-GP2 subunit interface of the LASV glycoprotein, thereby blocking pH-dependent viral fusion. As an aryl heteroaryl bis-carboxyamide derivative, losmapimod represents a novel chemical scaffold with anti-LASV activity, and it provides a new lead structure for the future development of LASV fusion inhibitors.

Keywords

Drug repurposing; Entry inhibitor; Lassa virus; Losmapimod; SSP-GP2.

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