Michael Norris, Ph.D.

What if we could act now to prevent a future, even deadlier pandemic?

FUNDED BY: The generosity of LJI Board Director (’16-’22) Tom Tullie and the Tullie family.

What was the goal of your SPARK project?

The emergence of viruses in the paramyxovirus family is a major concern for world health officials. These viruses are respiratory viruses with significant lethality and transmissibility—giving them pandemic potential. Included among paramyxoviruses are measles (infects over 7 million
people/year), parainfluenza (causative agent of croup), multiple livestock pathogens, as well as the deadly Nipah virus (kills 9 of 10 people infected). Sadly, no therapies exist for any paramyxovirus.

To stop these viruses, we need to develop drugs that can target a key viral protein called the matrix protein. This protein is the critical field marshal that builds new viruses and releases them from infected cells to spread throughout a patient. My aim was to advance the development of an antiviral drug that can target the matrix protein and stop viral assembly, halting the spread of the virus.

Did you face any challenges?

Due to the COVID-19 pandemic and the ongoing war in Ukraine (location of Enamine, the company that provides over 70% of the world’s stock of chemical building blocks and reagents), the synthesis of the compounds I identified in my work was significantly delayed. However, I was able to work with the SPARK program manager to obtain an extension and completed my project in May 2022.

SPARK project results:

Funds provided through the SPARK program gave me the opportunity to attend the High-Throughput Virtual Screening for Hit Finding and Evaluation
course taught by world experts in virtual screening at Schrödinger. This six-week immersive course provided me with the critical skills and hands-on training in the use of the Schrödinger small molecule drug discovery suite of software, and ultimately accelerated the discovery of candidate molecules in this research project. With these skills in hand, I used advanced computational algorithms to assess the druggability of key sites on measles and Nipah virus matrix proteins, called the dimer interface, the lipid-binding pocket, and the NTD pocket. Based on
key characteristics of the sites such as size and enclosure from the environment, I concluded that both the lipid-binding pocket and the NTD pocket are highly druggable sites.

From there, I began narrowing down a group of potential drug candidates to find those that could best target these sites and inhibit matrix proteins. I used an approach called “molecular docking” to predict a drug’s conformation, position, and its orientation within a protein binding site. This let me identify compounds with the best affinity and most favorablebtoxicity profiles for each site of interest on the matrix protein. Next, I tested these promising compounds for their ability to block matrix-driven assembly and budding. To do this, I
developed a novel cell-based budding assay for high-throughput screening at biosafety level 2.

What’s next for this project?

The results of this project have already been instrumental in publishing a study which made the cover story in Science Advances in June 2022. This study is the first-ever look at a key stage in the life cycles of measles and nipah viruses and reveals how future therapies might stop these viruses in their tracks.

What’s next for Michael?

I accepted a faculty position at the University of Toronto and started my lab there in Spring 2022.

My lab seeks to understand the structure and molecular assembly of pathogenic viruses, with special emphasis on paramyxoviruses and filoviruses. We combine structural biology, virology, molecular biology, and microscopy techniques to understand how the protein building blocks of these viruses interact with one another and self-assemble in a series of highly coordinated events that allow production of infectious viral particles. The three-dimensional molecular structures we reveal provide detailed information on the biological mechanisms driving viral assembly and will lay the foundation for the development of new, effective, and targeted therapeutic strategies.