The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase Revealed†
Larissa Dirr
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
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Dr. Ibrahim M. El-Deeb
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCorresponding Author
Dr. Patrice Guillon
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCindy J. Carroux
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCorresponding Author
Dr. Leonard M. G. Chavas
Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCorresponding Author
Prof. Mark von Itzstein
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorLarissa Dirr
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCorresponding Author
Dr. Ibrahim M. El-Deeb
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCorresponding Author
Dr. Patrice Guillon
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCindy J. Carroux
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCorresponding Author
Dr. Leonard M. G. Chavas
Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorCorresponding Author
Prof. Mark von Itzstein
Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Ibrahim M. El-Deeb, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Patrice Guillon, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Leonard M. G. Chavas, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 83, 22607, Hamburg (Germany)
Mark von Itzstein, Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, 4222 (Australia)
Search for more papers by this authorThe Australian Research Council (DP1094549, M.v.I. and P.G.) and the National Health and Medical Research Council (ID1047824, ID1071659, M.v.I.) are thanked for financial support. Griffith University is gratefully acknowledged for the award of a Griffith University Postdoctoral Award (I.M.E.D.). Both L.D. and C.J.C gratefully acknowledge the award of Griffith University Postgraduate Scholarships. We thank Dr. Thomas Haselhorst for useful discussions concerning the NMR experiments. We acknowledge the Photon Factory MX beam line crew for their precious help during data collection. We are particularly thankful to T. Senda and F. X. Gallat for hosting L.D. during the experiments and initial work on structure determination of the apo structure. The experiments were performed under the approval of the Photon Factory Program Advisory Committee (Proposal No. 2012G545).
Abstract
Human parainfluenza virus type 3 (hPIV-3) is one of the leading causes for lower respiratory tract disease in children, with neither an approved antiviral drug nor vaccine available to date. Understanding the catalytic mechanism of human parainfluenza virus haemagglutinin-neuraminidase (HN) protein is key to the design of specific inhibitors against this virus. Herein, we used 1H NMR spectroscopy, X-ray crystallography, and virological assays to study the catalytic mechanism of the HN enzyme activity and have identified the conserved Tyr530 as a key amino acid involved in catalysis. A novel 2,3-difluorosialic acid derivative showed prolonged enzyme inhibition and was found to react and form a covalent bond with Tyr530. Furthermore, the novel derivative exhibited enhanced potency in virus blockade assays relative to its Neu2en analogue. These outcomes open the door for a new generation of potent inhibitors against hPIV-3 HN.
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