Development of host target based antiviral strategies
Co-workers: Dominic Alonzi, Juan Bolivar Gonzalez, Bevin Gangadharan, Mario Hensen, Johan Hill, Michelle Hill, J.L. Kiappes, Abhinav Kumar, Joanna Miller, Nilanka Perera, Pietro Roversi, Kathryn Scott, Beatrice Tyrrell, Stephen Woodhouse
Dengue virus (DENV), Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Hepatitis B virus (HBV) collectively infect more than 550 million people worldwide. This group is developing antiviral therapies based on iminosugars to combat these and other viruses such as Ebola and influenza. The aim is to develop broad spectrum antivirals that prevent the emergence of viral escape mutants and can be used also in co-infections.
We are focusing in particular on interfering with the morphogenesis of HCV and HIV, on the host cytokine response to DENV infection, the structural biology of antiviral targets which include viral proteins (such as the HCV encoded p7 ion channel) as well as host cell proteins needed for the formation of infectious viruses (notably the enzymes constituting the calnexin cycle based protein folding quality control in the Endoplasmic Reticulum), and the development of a mass spectrometry based non-invasive diagnostic test for early stages of liver fibrosis (caused by HCV).
To achieve this, we work together with a number of local, national and international, academic, medical and industry partners. Members of my group are involved in several interdisciplinary projects, using transcriptomics, proteomics, mass spectrometry, x-ray crystallography, electron microscopy (EM), electron spin resonance (ESR), nuclear magnetic resonance (NMR), free oligosaccharide (FOS) and N-glycan analysis, electrophysiological techniques, as well as organic and medicinal chemistry. We also grow and kill viruses. We currently have an antiviral iminosugar compound in phase I clinical trials against DENV.
For more information about our research and group members, please visit www.zitzmannlab.com
Caputo A.T., D.S. Alonzi, L. Marti, I.B. Reca, J.L. Kiappes, W.B. Struwe, A. Cross, S. Basu, E.D. Lowe, B. Darlot, A. Santino, P. Roversi and N. Zitzmann, Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals, Proc Natl Acad Sci U S A, 2016, 113, p. E4630–E4638.
Sayce A.C., D.S. Alonzi, S.S. Killingbeck, B.E. Tyrrell, M.L. Hill, A.T. Caputo, R. Iwaki, K. Kinami, D. Ide, J.L. Kiappes, P.R. Beatty, A. Kato, E. Harris, R.A. Dwek, J.L. Miller and N. Zitzmann, Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases-Not Glycolipid Processing Enzymes, PLoS Negl Trop Dis, 2016, 10(3): p. e0004524.
Dalziel, M., M. Crispin, C.N. Scanlan, N. Zitzmann and R.A. Dwek, Emerging principles for the therapeutic exploitation of glycosylation, Science, 2014, 343(6166): p. 1235681.
Sayce, A.C., J.L. Miller and N. Zitzmann, Glucocorticosteroids as Dengue Therapeutics: Resolving Clinical Observations With a Primary Human Macrophage Model, Clin Infect Dis, 2013, 56(6): p. 901–903.
Gangadharan, B., M. Bapat, J. Rossa, R. Antrobus, D. Chittenden, B. Kampa, E. Barnes, P. Klenerman, R.A. Dwek and N. Zitzmann, Discovery of novel biomarker candidates for liver fibrosis in hepatitis C patients: a preliminary study, PLoS One, 2012, 7 (6): p. e39603.
Miller, J.L., R. Lachica, A.C. Sayce, J.P. Williams, M. Bapat, R. Dwek, P.R. Beatty, E. Harris and N. Zitzmann, Liposome-mediated delivery of iminosugars enhances efficacy against dengue virus in vivo, Antimicrob Agents Chemother, 2012, 56 (12): p. 6379-6386.
Figure 1: First ever crystal of UDP-glucose glycosyltransferase (UGGT)
Figure 2: Understanding the early transcriptomic response of human macrophages to dengue virus infection
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome