On April 29, Professor Zhan Peng and Associate Research Fellow Gao Shenghua of the School of Pharmaceutical Sciences, Shandong University, together with collaborators, published a research article entitled “Differential inhibition of Morbillivirus and Henipavirus polymerases by ERDRP-0519 and structure-guided inhibitor optimization” online in Cell. Leveraging the strengths of multidisciplinary integration, the study used structural biology as its foundation and medicinal chemistry as a core enabling approach to systematically delineate the cross-genus inhibitory mechanism of the small molecule ERDRP-0519 against paramyxoviral polymerases. Through precise iterative molecular optimization, the team developed a new-generation candidate molecule with substantially enhanced inhibitory activity against the highly pathogenic Nipah virus, providing critical support and a novel strategy for antiviral drug discovery targeting major emerging infectious diseases.

Associate Research Fellow Xue Lu and doctoral candidate Gui Jiacheng from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Associate Research Fellow Gao Shenghua from Shandong University; Research Technologist Gao Xiaoxiao from the Wuhan National Biosafety Laboratory; doctoral candidate Chang Tiancai from Guangzhou Medical University; and Pan Hainei from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, are co-first authors of the paper. Research Fellow Xiong Xiaoli from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Professor Zhan Peng and Research Fellow He Jun from the School of Pharmaceutical Sciences, Shandong University; Research Fellow Pei Rongjuan from the Wuhan Institute of Virology; and Research Fellow Chen Xinwen from the Guangzhou National Laboratory are co-corresponding authors. Professor Rong Lijun from the University of Illinois Chicago and Professor Richard K. Plemper from the Institute for Biomedical Sciences at Georgia State University provided important guidance and assistance for this work; Professor Liu Xinyong, Dean of the Institute of Innovative Drugs at Shandong University, provided strong support for the project.

The order Paramyxovirales comprises numerous pathogens that threaten human and animal health, including measles virus, Nipah virus, and peste des petits ruminants virus. Among these, Nipah virus has been listed by the World Health Organization as a “priority disease” and a “priority pathogen” because of its high case-fatality rate (40%–75%), capacity for cross-species transmission, and potential for human-to-human transmission; however, specific clinical therapeutics have long been lacking. The viral RNA-dependent RNA polymerase (RdRp) is a core target for viral replication, and the development of small-molecule drugs against this target represents a key direction for addressing the challenges of Nipah virus prevention and control.

ERDRP-0519 exhibits higher binding affinity for morbillivirus polymerases than for the Nipah virus polymerase; G671 enhances anti-Nipah virus activity by concomitantly occupying the “active site + RNA channel” and thereby establishing additional interdomain interactions.

The research team first discovered that ERDRP-0519, a measles virus polymerase inhibitor, exhibits cross-inhibitory activity against Nipah virus, although its anti-Nipah virus potency is much lower than its activity against measles virus. Cryo-electron microscopy structural analyses confirmed that this small molecule binds to a conserved pocket in the palm domain of the viral RdRp. By occupying the active center, it blocks the binding of the RNA template and nucleotides, thereby inhibiting viral RNA synthesis. The key determinant of the inter-genus difference in activity is that, when ERDRP-0519 binds to the Nipah virus polymerase, it must induce a larger conformational rearrangement of the binding pocket, which entails a higher energetic cost and results in markedly reduced binding affinity. Elucidation of this mechanism defined a precise target site for subsequent drug optimization.

(A) Structure of the ERDRP-0519–NiV polymerase complex; (B) optimization of ERDRP-0519 through a co-occupancy strategy targeting the “active site + RNA channel.”

On the basis of this structural mechanism, the medicinal chemistry team at the School of Pharmaceutical Sciences, Shandong University undertook the challenging task of iterative molecular optimization. Drawing on core medicinal chemistry principles and extensive experience in antiviral drug discovery, the team conducted multiple rounds of structural modification and activity validation through repeated exploration, thereby moving beyond the limitations of conventional optimization approaches. Taking advantage of the structural feature that the ERDRP-0519 binding site lies adjacent to the RNA elongation channel, the team innovatively proposed an “active site + RNA channel” co-occupancy design strategy, precisely identified the S5 fragment oriented toward motif F as the principal modification site, and introduced extension groups to mediate interdomain interactions, thereby compensating for the conformational deficiencies that limit binding of the parent molecule to the Nipah virus polymerase.

This process was not a simple chemical modification; rather, it involved structure-based rational design, multidimensional structure–activity relationship analyses, repeated trial-and-error, and iterative optimization. In this study, the medicinal chemistry team’s work spanned the full continuum from elucidation of target-binding mechanisms and structural optimization of lead compounds to the generation of candidate molecules. Through precise molecular design, the team compensated for the activity defects revealed by structural biology and used chemical strategies to address virus genus- and species-dependent differences, constituting an indispensable step in advancing the study from “mechanistic discovery” to “candidate drug.”

This study was supported by the National Key Laboratory for the Discovery and Utilization of Functional Components in Chinese Medicine and by the Antiviral and Major Chronic Disease Drug Discovery Team of the School of Pharmaceutical Sciences, Shandong University.