New Insights into the Structure and Function of a Key Viral Protein

Researchers from Harvard Medical School and Boston University's Chobanian & Avedisian School of Medicine have made significant progress in understanding the Nipah virus, a deadly bat-borne infection responsible for annual outbreaks since its discovery in 1999. Their findings, published in Cell, represent an important step toward developing treatments for a disease that currently lacks vaccines or effective therapies beyond supportive care.

The Nipah virus, carried by fruit bats, spreads through contaminated food, direct contact with infected animals or humans, and airborne droplets. Its high fatality rate, which ranges from 40% to 75% according to the Centers for Disease Control and Prevention (CDC), underscores its severity.

By comparison, the Ebola virus has a fatality rate of 25% to 90%, averaging 50%. The World Health Organization (WHO) has designated the Nipah virus as a priority pathogen due to its potential for significant outbreaks and the urgent need for prevention and treatment strategies.

Evidence suggests that even individuals with mild or nonspecific symptoms can transmit the virus, adding to its potential for widespread impact. In severe cases, the virus can cause encephalitis, an inflammation of the brain, or severe respiratory illness, both of which can result in long-term damage or death.

The recent study focused on the viral polymerase complex, a crucial set of proteins the virus uses to replicate its genetic material, spread, and infect host cells. The research provides a detailed three-dimensional structure of the polymerase, shedding light on how this essential component of the virus functions. Understanding the structure and behavior of the polymerase is a key step in identifying potential vulnerabilities that could be exploited for treatment.

“This study represents a key step toward understanding the inner workings of a dangerous virus,” said Rachel Fearns, co-corresponding author and Chair at Boston University Chobanian & Avedisian School of Medicine. “Identifying how the polymerase switches on and off different enzymatic activities needed for replication could transform our approach to combating this pathogen.” Jonathan Abraham, co-corresponding author and associate professor at Harvard Medical School, emphasized, “This new understanding can help us identify functional properties of the polymerase structure that could be leveraged as drug targets.”

The researchers used cryo-electron microscopy to visualize the polymerase at a molecular scale and engineered mutations in the enzyme to observe how structural changes affected its functions.

These experiments provided valuable insights into the polymerase's unique and shared characteristics compared to other viral polymerases, which could inform the development of broad-spectrum antiviral treatments. Heesu Kim, co-first author and researcher at Boston University, highlighted the study’s implications: “Our study provides critical insights that have the potential to inform the development of broad-spectrum antivirals.”

Although no drugs specifically target the Nipah virus, researchers at Georgia State University have developed an oral medication candidate for related viruses. However, this drug is ineffective against Nipah itself. To address this gap, the study identified a particular region of the viral polymerase as a potential drug target. By understanding the structural features of this region, researchers can design small-molecule inhibitors to disrupt the polymerase’s function and make the virus treatable.

“By openly sharing our data, we hope to encourage additional research into this deadly pathogen,” said Side Hu, co-first author, and postdoctoral researcher in the Abraham Lab. “Collaboration is key to moving the field forward.”

This study provides a critical foundation for developing targeted therapies against the Nipah virus. By unraveling the structure and function of the viral polymerase, researchers have made strides toward addressing one of the world’s most dangerous pathogens. Ongoing collaboration and research will be essential in translating these findings into effective treatments and preventing future outbreaks.