Designing antivirals for shape-shifting viruses

But new research utilizes an innovative computational modeling approach to capture the complex and diverse shapes that viral proteins can adopt. The work will be presented at the 69th Biophysical Society Annual Meeting, to be held February 15 -- 19, 2025 in Los Angeles.

This new approach, implemented in the open-source Integrative Modeling Platform (IMP) software, combines various experimental techniques, including different ways of visualizing and measuring real viruses (via cryo-electron microscopy and mass spectrometry), as well as molecular dynamics simulations, to create a comprehensive picture of a virus' dynamic behavior.

Kenneth Huang, PhD, a postdoctoral computational structural biologist working in the labs of Ignacia Echeverria and Andrej Sali at the University of California, San Francisco, led the project. He compared viruses to nightmare houses, where depending on the conditions, the interior could be completely different. To design antivirals, they are trying to figure out "the fastest way to demolish this house with the least number of whacks with an ax," Kenneth said.

So far, they have applied their approach to a key protein involved in replication of the COVID-19 virus, named Nsp2. Using their model, they've built a detailed picture of Nsp2 -- not just as a single rigid structure, but as a collection of the different, flexible shapes it can adopt. Kenneth was surprised at how much Nsp2 changes "in response to whatever is around it."

By understanding this flexibility and the different shapes Nsp2 can adopt, Kenneth and colleagues can use this new tool to predict where to target drugs that would best block its replication, and how to design those drugs. Though we already have antivirals for COVID-19, in a situation like a pandemic, tools that help design antiviral drugs as efficiently as possible could save countless lives.

Often, antivirals and other drugs are discovered by drug screens, in which companies test many thousands of molecules to see if they have the intended effect. "So, they just basically use brute force and keep screening compounds until they eventually find something that works," Kenneth said. This 'brute force' method can be expensive and take time, he explained.

By instead designing compounds that are specifically targeted for a virus, you can eliminate a lot of the time, staff and money required in screening thousands of compounds. This approach has the potential to pave the way for more potent and targeted therapies against a wide range of viral infections. "We want to be able to kill these viruses so that they don't make people sick," Kenneth said.