Among the many RNA viruses that continue to threaten human and animal health, orthobunyaviruses occupy a particularly concerning position. This large family of segmented, negative-sense RNA viruses includes pathogens responsible for encephalitis, febrile illness, and hemorrhagic disease — among them the La Crosse, Oropouche, and Schmallenberg viruses — yet no licensed antiviral therapy exists for any of its members. The viral RNA-dependent RNA polymerase (RdRp) has long been recognized as an attractive drug target, given its indispensable role in both genome replication and transcription and its structural divergence from host cell enzymes. Until now, however, the molecular architecture of the orthobunyavirus polymerase during active RNA synthesis has remained unresolved.
A study by Tang, Kuang, and colleagues from the Wuhan Institute of Virology, Chinese Academy of Sciences, published in Nature Communications on May 15, 2026, addresses this gap with unusual completeness. Using the Ebinur Lake virus (EBIV) — a representative orthobunyavirus — as their model system, the authors first established robust in vitro enzymatic activity assays for the isolated polymerase and then determined cryo-electron microscopy structures in three distinct functional states: the apo form, the elongating complex, and the inhibitor-bound complex. The resulting structural series offers, for the first time, a dynamic picture of how this class of polymerase operates at near-atomic resolution.
The structures reveal a multi-domain RdRp architecture whose conformational landscape shifts substantially between states. Two elements prove particularly noteworthy. The first is the prime-and-realign (PR) loop, a structural feature that undergoes marked conformational transitions during the transition from initiation to elongation — a mechanism by which the polymerase repositions the nascent RNA strand to permit processive synthesis. The second is a unique β-hairpin that physically connects the zinc-binding domain (ZBD) to the RdRp catalytic core, a structural bridge not previously described in this viral family and likely to play a regulatory role in template engagement. Both elements were validated functionally through correlated in vitro enzymatic and cell-based minireplicon assays.
Perhaps the most clinically consequential finding concerns suramin, a century-old antiparasitic drug that has periodically attracted attention as a broad-spectrum antiviral. The suramin-bound structure reveals two distinct inhibitory binding sites on the EBIV polymerase: one that sterically clashes with the vRNA promoter, physically preventing the viral genome from engaging the enzyme; and a second that directly occludes the RNA template strand binding channel, blocking the entry of the genome template into the active site altogether. The simultaneous targeting of two mechanistically distinct points of the replication cycle by a single small molecule is a striking finding, and one that provides a concrete structural rationale for suramin’s previously observed but poorly understood antiviral activity.
The translational implications are significant and immediate. The structural framework established here — spanning apo, elongating, and inhibitor-bound states — constitutes precisely the type of multi-state atomic map that medicinal chemists require to pursue rational drug design. Suramin itself is poorly suited for clinical antiviral use due to its toxicity profile and limited selectivity, but the identification of its two binding pockets provides defined coordinates for the design of more selective, lower-toxicity derivatives or entirely novel scaffolds targeting the same sites. Moreover, given the conserved domain architecture across orthobunyaviruses, these structures may inform antiviral strategies well beyond EBIV, extending potentially to pathogenic members of the family responsible for human disease.
Important caveats remain. The study is conducted entirely in vitro and in cell-based replicon systems; the transition to animal models and ultimately to clinical candidates will require substantial additional work, including demonstration of antiviral efficacy in vivo and resolution of the selectivity challenges inherent in targeting an RNA polymerase. The degree of structural conservation across the diverse orthobunyavirus genus also remains to be systematically assessed. These are, however, the natural next steps in a well-defined research program rather than fundamental obstacles, and this work represents a qualitative advance in the structural virology of an underserved and epidemiologically significant viral family.
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