Scientists mapped the 3-dimensional structure of a critical component in Nipah virus, "a bat-borne, zoonotic RNA virus that is highly pathogenic in humans," with a fatality rate "ranging from 40% to 70%," according to research.

The study, published in Cell, determined the "2.3 Å cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L) and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase." Researchers identified key structural features, including the "palm insert, zinc fingers, and P4 extension," which play critical roles in viral replication and transcription.

"Although several nsNSV polymerase structures are available, how the features identified within them facilitate different polymerase functions is generally poorly defined, and it is not fully understood how the polymerase is regulated to ‘switch on’ and ‘switch off’ the different enzymatic activities that are required for mRNA transcription versus genome replication," said Rachel Fearns, PhD, chair and Ernest Barsamian Professor of Virology, Immunology & Microbiology at Boston University Chobanian & Avedisian School of Medicine.

The research team, led by investigators at Harvard Medical School and Boston University, used cryo-EM to visualize the polymerase complex at high resolution and "identify features of the polymerase that are required for transcription and/or genome replication, providing information that has the potential to aid rational design of antiviral molecules against NiV." Scientists from Hubei University of Technology, University of Massachusetts, Shanghai University, Brigham & Women’s Hospital, and the Broad Institute also contributed to the study.

"This new understanding can help us identify the functional properties of the polymerase structure that could be leveraged as drug targets," said co-corresponding author Jonathan Abraham, MD, PhD, associate professor of microbiology at Harvard Medical School and investigator at the Howard Hughes Medical Institute.

Nipah virus can spread through "droplet-based transmission through coughing," and with its high mortality rate, "NiV is on the World Health Organization Research & Development Blueprint list of priority diseases for which there is an urgent need for accelerated research and countermeasure development." There are currently "no vaccines or antiviral against NiV infection."

The researchers identified a structural reason why the broad-spectrum paramyxovirus inhibitor GHP-88309 is ineffective against Nipah virus, specifically due to "a histidine in the predicted drug binding site (H1165) in NiV L [that] has been implicated in resistance." The study further explains, "Introducing the H1165Y substitution into NiV L, which mimics the residue that is naturally present in susceptible polymerases, renders NiV L susceptible to GHP-88309 inhibition, with the EC50 value decreasing by 60-fold (5.3 μM)."

The Nipah virus polymerase plays two essential roles: "The NiV genome is a single strand of negative-sense RNA that is transcribed and replicated by the viral polymerase. During transcription, the polymerase generates capped and polyadenylated monocistronic mRNAs, corresponding to each of the viral genes. During replication, it produces full-length, encapsidated replicative RNAs, which are uncapped and lack a poly A tail."

First identified in Malaysia in 1998, Nipah virus has caused "spillover events from bats into humans almost annually in Bangladesh," with outbreaks also reported in India, the Philippines, and Singapore. The study was funded by the Bill & Melinda Gates Foundation, with cryo-EM data collected at Harvard’s Cryo-Electron Microscopy Center for Structural Biology.

While this structural mapping represents significant progress, the study notes that "additional studies will be required to determine whether binding of ligands, including nucleotides and/or nucleic acids, causes these regions to become ordered."

"We hope that these findings will spark interest and stimulate additional research by others, enabling new insights into a deadly pathogen," said Side Hu, PhD, co-first author and postdoctoral researcher in the Abraham Lab.

Full disclosures can be found in the study.

Reference:

Harvard Medical School. Scientists uncover structure of critical component in deadly Nipah virus. Harvard Medical School News. January 20, 2025. Accessed February 7, 2025. https://hms.harvard.edu/news/scientists-uncover-structure-critical-component-deadly-nipah-virus