Michael Norris, Ph.D.

What can we do *now* to prevent a future, even deadlier pandemic?

FUNDED: JANUARY 2021
FUNDED BY: the generosity of The Tullie Family

This year, the global economy was shut down by a pandemic caused by a virus for which humanity has no drugs available. To ensure we avoid another disaster like 2020, we must develop antiviral drugs to combat the next viral pandemic. Health experts believe the next pandemic could be caused by a member of the paramyxovirus family. This sprawling family of viruses includes measles, which still infects over 7 million people every year; parainfluenza, which causes croup; multiple livestock pathogens that cost the industry >$100 million annually; and the fairly new but lethal Nipah virus, which kills 9 of 10 people infected. All paramyxoviruses are highly infectious. The infectiousness of measles, for example, is unmatched: a single cough in a room of 100 unvaccinated people will infect 90 of those 100 people. We have no therapies to treat paramyxovirus infections and a paramyxovirus pandemic will be catastrophic.

Despite their deadly potential, paramyxoviruses carry only 6 genes. This is all that is required to copy themselves thousands of times. A key part of the paramyxovirus machinery is the matrix protein, which acts as a critical field marshal that gathers and guides the assembly of viral components to build new viruses and release them from the infected cell. If we could develop an antiviral drug that targets the matrix protein, we could arrest viral assembly and in turn, halt virus spread.

I recently determined the high-resolution molecular structures of several different paramyxovirus matrix proteins, learned how they hijack the human cell membrane, and identified three key vulnerable sites shared by many paramyxoviruses. A drug targeting one of these sites could block all or many paramyxoviruses. LJI has filed a provisional patent application on this concept. I now seek to find the candidate molecules to protect and capitalize on these discoveries. In this project, I will screen and identify small molecule drugs that bind into these sites to block the assembly and spread of new viruses. I will then test them against numerous paramyxoviruses relevant for human and livestock health.

Sixth-Month Project Update

Paramyxoviruses include some of the most infectious and deadly viruses known to mankind—and we have no way to stop them. One of the most important pieces of these viruses is the matrix protein, also known as M. In an infected cell, the virus manufactures thousands of copies of M as it begins making copies of itself. If we could develop an antiviral drug that targets the M protein interaction with the membrane lipid, we could stop infections in their tracks.

For my SPARK project, I built on my previous success in solving the 3-D structure of a paramyxovirus M protein in complexes with a membrane lipid. This structure became my “blueprint” to find drugs that can inhibit the membrane binding process. I used a technique called virtual drug screening to evaluate millions of drugs for their potential to bind M. Through this process, I narrowed down the list of over 3.2 million drugs to a few thousand.

In the coming months I will begin the next phases in the virtual screening workflow by undertaking molecular docking of the compounds identified from shape screening and computationally determining if they can bond with the M protein.