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Nat Commun2025;16(1):8930.October 8, 2025Journal Article

Combined crystallographic fragment screening and deep mutational scanning enable discovery of Zika virus NS2B-NS3 protease inhibitors.

Xiaomin Ni1, R Blake Richardson2, Andre Schutzer Godoy3, Matteo P Ferla4, Caroline Kikawa5,6,7, Jenke Scheen8, William W Hannon9,10, Eda Capkin11,12, Noa Lahav13, Blake H Balcomb11,12, Peter G Marples11,12, Michael Fairhead4, SiYi Wang4, Eleanor P Williams4, Charles W E Tomlinson11,12, Jasmin C Aschenbrenner11,12, Ryan M Lithgo11,12, Max Winokan11,12, Charline Giroud4, Isabela Dolci3, Rafaela Sachetto Fernandes3, Glaucius Oliva3, Anu V Chandran11,12, Mary-Ann Xavier11,12, Martin A Walsh11,12, Warren Thompson11,12, Jesse D Bloom7,14, Nathaniel T Kenton15, Alpha A Lee15, Annette von Delft4, Haim Barr13, Karla Kirkegaard16,17, Lizbé Koekemoer4, Daren Fearon11,12, Matthew J Evans18, Frank von Delft19,20,21,22
1Centre for Medicines Discovery, University of Oxford, NDM research Building, Roosevelt Dr, Headington, Oxford, UK. xiaomin.ni@cmd.ox.ac.uk.
2Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3São Carlos Institute of Physics, University of São Paulo, Av. João Dagnone, São Carlos, 13563-120, Brazil.
4Centre for Medicines Discovery, University of Oxford, NDM research Building, Roosevelt Dr, Headington, Oxford, UK.
5Medical Scientist Training Program, University of Washington, Seattle, WA, USA.
6Department of Genome Sciences, University of Washington, Seattle, WA, USA.
7Division of Basic Sciences, Fred Hutch Cancer Center, Seattle, WA, USA.
8Open Molecular Software Foundation, Davis, CA, 95618, USA.
9Division of Basic Sciences, Computational Biology Program, and Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
10Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA.
11Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, Oxfordshire, UK.
12Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, UK.
13The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, 7610001, Israel.
14Howard Hughes Medical Institute, Seattle, WA, USA.
15PostEra Inc, 1 Broadway, Cambridge, MA, 02142, USA.
16Department of Genetics, Stanford University, Palo Alto, CA, USA.
17Department of Microbiology and Immunology, Stanford University, Palo Alto, CA, USA.
18Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. matthew.evans@mssm.edu.
19Centre for Medicines Discovery, University of Oxford, NDM research Building, Roosevelt Dr, Headington, Oxford, UK. frank.vondelft@cmd.ox.ac.uk.
20Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, Oxfordshire, UK. frank.vondelft@cmd.ox.ac.uk.
21Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, UK. frank.vondelft@cmd.ox.ac.uk.
22Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg, South Africa. frank.vondelft@cmd.ox.ac.uk.
PubMed PMC DOI PDF

Abstract

The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 46 fragments with diverse scaffolds…

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