Emerging arenaviruses cause several hundred thousand infections per year with thousands of deaths. There are currently no licensed vaccines against these viruses and therapeutic options are limited, making the development of novel strategies for therapeutic intervention an urgent need. Fatal arenavirus infection is characterized by rapid viral multiplication that overwhelms the patient’s immune defenses and results in uncontrolled infection, shock and death. Drugs targeting different steps in the arenavirus life cycle will lower the viral load, providing the patient’s immune system a window of opportunity to control the infection and clear the virus. In our applied research, we target individual steps of the arenavirus life cycle using recombinant surrogate systems that are implemented in small molecule drug screening. Candidate drugs are the evaluated for anti-viral activity in our infection models.
Identification of drugs targeting different steps of the arenavirus life cycle: using recombinant surrogate systems as platforms for small molecule drug screening, we seek to identify drugs targeting viral entry and the biosynthesis and maturation of the viral envelope glycoprotein required for viral assembly and budding.
Collaborators: Prof. Juan Carlos de la Torre (Scripps Research Institute, La Jolla, USA), Dr. Christina Spiropoulou (Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, USA).
Funding: Swiss National Science Foundation Grant Nr. 310030-149746/1 (Kunz) "Host cell invasion by Lassa virus" and University of Lausanne.
During our research on arenaviruses, we identified the proprotein convertase subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P) as a promising target for anti-viral intervention. SKI-1/S1P is implicated in the proteolytic processing of the envelope glycoproteins of all known arenaviruses and other emerging viruses. Inhibitors of SKI-1/S1P show strong anti-viral activity, validating SKI-1/S1P as a “druggable” target for therapeutic intervention. Importantly, SKI-1/S1P is linked to other major human pathologies, including metabolic disorders such as hypercholesterolemia, vascular diseases, and cancer making it an interesting “druggable” target for therapeutic intervention. Our work on the biochemistry of SKI-1/S1P revealed novel and unexpected features of this important enzyme, its mechanism of action, and evolution. We developed a novel cell-based molecular sensor for SKI-1/S1P that recapitulates key features of authentic substrates. This sensor is currently implemented in drug screens to discover novel inhibitors for SKI-1/S1P, cellular factors that modulate SKI-1/S1P activity, and the discovery of new substrates.
SKI-1/S1P is involved in viral infection and major human disorders: the role of SKI-1/S1P in the processing of the viral envelope glycoprotein of arenaviruses (A). Our novel cell-based sensor to detect SKI-1/S1P activity published on the cover of the Journal of Biological Chemistry in 2014 (B).
Collaborators: Prof. Nabil G. Seidah (Laboratory of Biochemical Neuroendocrinology, IRCM, Montreal, Canada), Prof. Laura Cendron and Prof. Giuseppe Zannotti (University of Padua, Italy), Prof. Majid Khatib (INSERM, UMRS 1029, Talence, France).
Funding: Research Grant Novartis Foundation for Biomedical Research Grant 14B086 "Targeting subtilisin kexin isozyme 1/site 1 protease for therapeutic intervention " and University of Lausanne.