IFITMs: Natural viral fusion inhibitors

• Applicant: Professor Herre Jelger Risselada, Ph.D.
• Subject Area: Biophysics
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 374976405

My goal is to elucidate how Interferon-induced transmembrane proteins (IFITMs) restrict viral entry. IFITMs are currently one of the most broadly acting and clinically relevant anti-viral molecules. To allow the viral genome to enter and infect the host viruses {\it must} fuse with either the endosomal membrane or plasma membrane. IFITM evidently inhibits a late step in the viral fusion mechanism while simultaneously leaving other essential, functional fusion reactions unaffected. What makes this project truly unique and original is that it directly focuses on how viral fusion can be inhibited both efficiently and selectively -- thereby being directly inspired by Nature. Being a relatively simple molecule, the ability to design improved molecular mimics of IFITM is realistic and will have far-reaching implications. If IFITMs increase a free energy barrier within the fusion reaction, and specifically for viral fusion, detailed molecular insights of the fusion reaction are the only approach that can yield fundamentally new insights. To this aim, I will apply molecular dynamics simulations in combination with state-of-the-art free energy calculation methods to address how IFITM molecules alter the free energy landscape of viral fusion and which of IFITM's molecular characteristics determine viral restriction. Elucidating IFITM's restriction mechanism will help to generate novel therapeutic strategies that could be applied against a broad range of both human and animal pathogens, and will further our understanding of membrane fusion, a fundamental process for all life on earth.

• DFG Programme: Research Grants