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  3. A high-throughput cell-based screening method for Zika virus protease inhibitors discovery

A high-throughput cell-based screening method for Zika virus protease inhibitors discovery

  • SLAS Discov. 2024 May 23:100164. doi: 10.1016/j.slasd.2024.100164.
Paulina Duhita Anindita 1,  Yuka Otsuka 2,  Simon Lattmann 3,  Khac Huy Ngo 1,  Chong Wai Liew 4,  CongBao Kang 5,  Reuben S Harris 6,  Louis Scampavia 2,  Timothy P Spicer 7,  Dahai Luo 8
Affiliations

Affiliations

  • 1 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
  • 2 Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Florida, United States.
  • 3 NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
  • 4 NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  • 5 Experimental Drug Development Centre, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 6 Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, Texas, United States; Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, Texas, United States.
  • 7 Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Florida, United States. Electronic address: spicert@ufl.edu.
  • 8 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore; National Centre for Infectious Diseases, Singapore, Singapore. Electronic address: luodahai@ntu.edu.sg.
PMID: 38796112 DOI: 10.1016/j.slasd.2024.100164
Abstract

Zika virus (ZIKV) continues to pose a significant global public health threat, with recurring regional outbreaks and potential for pandemic spread. Despite often being asymptomatic, ZIKV infections can have severe consequences, including neurological disorders and congenital abnormalities. Unfortunately, there are currently no approved vaccines or Antiviral drugs for the prevention or treatment of ZIKV. One promising target for drug development is the ZIKV NS2B-NS3 protease due to its crucial role in the virus life cycle. In this study, we established a cell-based ZIKV protease inhibition assay designed for high-throughput screening (HTS). Our assay relies on the ZIKV protease's ability to cleave a cyclised firefly luciferase fused to a natural cleavage sequence between NS2B and NS3 protease within living cells. We evaluated the performance of our assay in HTS setting using the pharmacologic controls (JNJ-40418677 and MK-591) and by screening a Library of Pharmacologically Active Compounds (LOPAC). The results confirmed the feasibility of our assay for compound library screening to identify potential ZIKV Protease Inhibitors.

Keywords

HTS; Zika virus; cell-based assay; protease inhibitors.

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