Avoiding Drug Resistance by Understanding Evolution of Viruses

BUFFALO, N.Y., August 3, 2021 — Markets prices aside, the cost created by drug resistance to effective drugs is numbered in millions of lives and billions of dollars.

During the American Crystallographic Association’s 71st annual meeting, Structural Science Awakens, which will be held virtually July 30-Aug. 5, Celia Schiffer, from the University of Massachusetts Medical School, will talk about her lab’s work with virus substrate recognition as a method to avoid drug resistance. Her presentation, “Constraining Evolution — Avoiding Drug resistance: Lessons from Viruses,” will be held Tuesday, Aug. 3 at 1:20 p.m. Eastern.

Schiffer and her team expanded their work on HIV and the hepatitis C virus (HCV) to include human T-cell lymphotropic virus type 1 (HTLV-1) and SARS-CoV-2, the virus that causes COVID-19.  

“There are a variety of mechanisms by which evolution occurs,” she said. “In viruses, it is often because of the infidelity of a viral polymerase, which introduces mistakes into the genome that may be useless or might have a selective advantage in the presence of a drug that confers drug resistance.

“All of these viruses have one or more viral proteases, but they are different kinds of proteases with different kinds of chemistry, and the substrate sequences of their cleavage sites. HIV and HTLV-1 are aspartyl proteases. HCV is a serine protease. Both of the proteases in SARS-CoV-2 (Mpro and PLpro) are cysteine proteases.”

Resistance occurs when the balance between substrate recognition and cleavage is favored over enzyme inhibition. Her lab discovered that designing robust inhibitors to fit within the substrate envelope tips this balance toward decreasing the probability of resistance, as mutations would also impact substrate recognition. 

To further understand more complex mechanisms of resistance Schiffer’s team is using molecular dynamics and machine learning to explain the impact of resistance mutations. By analyzing how the virus cleaves its substrates, scientist can design drugs to avoid potential evolutionary changes and improve the chance of avoiding drug resistance.

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ABOUT AMERICAN CRYSTALLOGRAPHIC ASSOCIATION

The American Crystallographic Association, Inc. is a nonprofit, scientific organization of more than 1,000 members in more than 35 countries. The ACA was founded in 1949 through a merger of the American Society for X-Ray and Electron Diffraction (ASXRED) and the Crystallographic Society of America (CSA). The objective of the ACA is to promote interactions among scientists who study the structure of matter at atomic (or near atomic) resolution. These interactions will advance experimental and computational aspects of crystallography and diffraction. Understanding the nature of the forces that both control and result from the molecular and atomic arrangements in matter will help shed light on chemical interactions in nature.

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