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Lecture

Chemical Biology lecture - Human Norovirus: The winding road to entry inhibition

  • Dr. Alvaro Mallagaray (University of Lübeck)
Date
Thursday 7 November 2019
Time
Location
Gorlaeus Building
Einsteinweg 55
2333 CC Leiden
Room
EM1.09

Dr. Alvaro Mallagaray studied Organic Chemistry at the University of San Pablo (Madrid, Spain) as well as Emotional Intelligence at the University Camila José Cela. He did a PhD in Medicinal Chemistry, Organometallic & Nuclear Magnetic Resonance spectroscopy at the University of San Pablo. He was a visiting doctor in Naples and since 2013 works as a researcher at the University of Lübeck in Germany. He studies protein-sugar interactions with experimental and computational techniques in relation to norovirus infections.

If you want to meet Dr. Mallagaray you can contact Marcellus Ubbink (m.ubbink@chem.leidenuniv.nl).

Abstract

Infection with human norovirus (hNoV) is the leading cause of acute gastroenteritis worldwide. Efforts to develop broadly active vaccines have been thwarted by the ability of noroviruses to constantly evolve, generating new strains every 2-4 years. The picture of how hNoV infects host cells is becoming increasingly complex, as histo blood group antigens (HBGAs), bile acids and bivalent ions have been shown to be required or to modulate viral infectivity.

We use protein NMR experiments supported by mass spectrometry, crystallography and molecular dynamics to study HBGA and bile salts binding to prevalent hNoV strains. Binding epitopes, dissociation constants and protein allosteric networks associated to ligand binding can be efficiently dissected at atomic resolution. On the road of the discovery of entry inhibitors against hNoV,[1] unexpected results unraveled hitherto unknown features about hNoV. In particular, in this lecture we will discuss:

  • How HBGA recognition can be modulated in some hNoV strains by a spontaneous posttranslational modification (PTM). Sequence conservation and surface-exposition of this PTM
  • suggest an important role in infection and immune recognition for GII.4 human norovirus strains.[2]
  • Recently, it has been reported that norovirus infection can be significantly enhanced by bile salts in cell culture. Here, we will show how NMR and molecular dynamics have been used to identify a previously unknown low-affinity bile acid binding site in hNoV.[3]
  • Allosteric inhibition represents a powerful alternative to competitive inhibition for the development of entry inhibitors. We will discuss our latest efforts towards the identification of promising leads against hNoV using a combination of protein NMR and docking.[4]

References

  1. Bücher, K.S. et al. BioMacromolecules 2018, 19, 3714-3724.
  2. Mallagaray, A. et al. Nature Communications, 2019, 10, Article number: 1320
  3. Creutznacher, R. et al. ChemBioChem, 2019, in press.
  4. a) Mallagaray, A. et al. Angew. Chem. Int. Ed. 2015, 54, 12014-12019. b) Mallagaray, A. et al. Glycobiology 2016, 1, 80-86.
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