Researchers at Penn Medicine are using advanced imaging techniques to better understand how viruses like influenza replicate, potentially opening new pathways for drug development. The team is applying cryogenic electron microscopy (cryoEM) and cryo-electron tomography (cryoET) to study the molecular processes that occur during viral infection.
The influenza virus, which causes hundreds of thousands of deaths worldwide each year, invades human cells and uses its genomic RNA to direct the production of viral proteins. These proteins assemble into new viruses that continue the cycle of infection. Current therapies often target surface proteins on the virus, but these evolve rapidly, reducing their effectiveness over time. Researchers hope that by focusing on viral replication—an aspect that changes less frequently—they can develop treatments or vaccines with longer-lasting efficacy.
Viral replication takes place inside a ribonucleoprotein complex, a structure made up of multiple proteins and an RNA-copying enzyme called polymerase. This enzyme produces millions of copies of viral RNA and helps generate messenger RNA (mRNA), which is used to make more viral proteins.
Imaging this complex has been challenging because parts of it are highly flexible and move around, making it difficult for standard analysis software to create clear images. To address this issue, Ruchao Peng, PhD, working with Yi-Wei Chang, PhD, developed two solutions: creating more rigid lab-made complexes for imaging with cryoEM and using cryoET to capture images of the flexible parts.
By combining thousands of images from both methods, the researchers were able to create detailed visualizations showing how the ribonucleoprotein complex operates. They observed in detail how the polymerase moves along a double-stranded helix structure during transcription—the process where viral RNA is converted into mRNA.
The research revealed that throughout transcription, most of the viral RNA remains protected within the helix. Only a small segment is exposed at any time as a template for mRNA production. This protection helps prevent degradation by host enzymes and preserves the machinery needed for repeated replication cycles.
A key finding was the identification of a binding pocket between subunits in the helical structure—a potential vulnerability in the virus’s replication process. According to their study published in Science in May 2025, inserting a small molecule into this pocket could block polymerase activity and stop viral replication. The team has already identified several candidate compounds that may work in this way.
Further studies published in Nature Structural and Molecular Biology in February 2025 provided near-atomic resolution images pinpointing where drugs could bind within these channels. “We are doing drug discovery, but on a completely different level, starting from a structural perspective,” Rocereta said.
Penn Medicine researchers are also applying these imaging methods to cancer research. In Ronen Marmorstein’s laboratory, Kollin Schultz used cryoEM to study fatty acid synthase—a protein complex essential for cell growth but also exploited by tumors for building cell membranes. Schultz’s work provided new insights into how this enzyme functions and may inform future efforts to develop inhibitors targeting cancer or fatty liver disease. This research was conducted in collaboration with Kathryn E. Wellen at Penn’s Abramson Family Cancer Research Institute and published in Nature in February 2025.
Marmorstein highlighted Penn’s collaborative environment as crucial for advancing such interdisciplinary research: “I think what's special about Penn is that it's really highly collaborative,” Marmorstein said. “People like to work together. This makes doing science a lot more fun, and it allows your work to go beyond where it would normally be able to go at an institution where the interactions were more limited.”
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