Seino A. K. Jongkees
AIMMS Amsterdam Institute of Molecular and Life Sciences
Antiviral Peptides from mRNA Display Antiviral Peptides from mRNA Display
SESSION 14: NOVEL ADVANCES IN PEPTIDE CHEMISTRY
Thursday, June 29, 2023, at 02:25 pm - 02:45 pm
The current Covid-19 pandemic dramatically illustrates the need to find new anti-viral agents, and underscores the importance of finding these agents before they are needed. Influenza remains a pandemic threat, and resistance is building to many of the current anti-influenza treatments on the market. While antibodies are being explored for treatment for both of these viruses, they are not practical to deploy at a population level.
As an alternative approach that we believe captures many of the advantages of antibodies in a synthetically tractable molecule, we have used mRNA display under a reprogrammed genetic code, RaPID system, to find antiviral peptides with broad protective effects against infection by both influenza, H1 and H5 cross-reactivity,1 and sarbecoviruses, SARS and SARS-CoV-2 cross-reactivity.2
Hydrogen-Deuterium exchange footprinting of our anti-influenza peptides revealed a surprising preference for these to bind to the more conserved "stem" region of the protein, where the "head" region is typically dominant for antibody binding. Passaging the virus with one of these inhibitors does lead to resistance, but raising new peptides against the resistant variant gives new hits that force the virus to compromise fitness to escape when administered together with the original hits.
A cryo-EM structure of our anti-coronavirus peptide reveals that it is binding to a highly conserved and previously unexploited ternary site between the S1A, S1B, and S2 domains. Overall these molecules emphasize the promise of small macrocyclic peptides in combating new viral outbreaks by targeting viral proteins on the particle surface.
1. Pascha, M. N., Thijssen, V., Egido, J. E., Linthorst, M. W., Lanen, J. H. Van, Dongen, D. A. A. Van, Hopstaken, A. J. P., Kuppeveld, F. J. M. Van, Snijder, J., Haan, C. A. M. De, and Jongkees, S. A. K. Inhibition of H1 and H5 Influenza A Virus Entry by Diverse Macrocyclic Peptides Targeting the Hemagglutinin Stem Region. ACS Chem. Biol. 2022, 17 (9), 2425–2436.
2. Thijssen, V., Hurdiss, D. L., Debski-Antoniak, O. J., Spence, M. A., Franck, C., Norman, A., Aggarwal, A., Mokiem, N. J., van Dongen, D. A. A., Vermeir, S. W., Liu, M., Chatziandreou, M., Donselaar, T., Du, W., Drulyte, I., Bosch, B. J., Snijder, J., Turville, S. G., Payne, R. J., Jackson, C. J., van Kuppeveld, F. J. M., and Jongkees, S. A. K. A Broad-Spectrum Macrocyclic Peptide Inhibitor of the SARS-CoV-2 Spike Protein. bioRxiv, 2022
I did my bachelors degrees in chemistry, biochemistry and philosophy at the University of Otago, in my homeland of New Zealand. From there I threw myself across the pacific to carry out my Ph.D. with Professor Stephen Withers at the University of British Columbia, Canada. Next I crossed the pacific again to pursue a JSPS post-doctoral position at the University of Tokyo, Japan, under the guidance of Professor Hiroaki Suga. Heading back to my roots, I then took up an assistant professorship position at Utrecht University before moving the group to our current home at VU Amsterdam. My research interests are guided by a desire to understand how living systems work on a chemical level. I am fascinated by the idea of a collection of intricate and complex reactions coming together to create something like a cell, or even a whole organism.