Enhanced Antiviral Activity of Novel Umifenovir Derivatives against SARS-CoV-2: Insights from an International Collaborative Study
Year: 2026
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Despite the availability of vaccines and treatments for COVID-19, the emergence of new SARS-CoV-2 variants continues to challenge vaccine-induced immunity, emphasizing the need to develop antiviral therapies to combat these variants and other viruses. Umifenovir (UMF), marketed as Arbidol, is a broad-spectrum antiviral drug approved in Russia and China for influenza viruses A and B. Recent studies have suggested its potential against SARS-CoV-2, demonstrating its ability to inhibit viral replication and obstruct viral entry by targeting the spike protein, despite having low oral bioavailability and short half-life. In this work, we conducted an initial antiviral screening that identified a hit compound (a UMF analogue), followed by the rational design, synthesis, and evaluation of novel UMF derivatives against SARS-CoV-2. This process employed generative models and structure–activity relationship studies (SAR), focusing on the UMF binding site on the S2 subunit of the spike protein. The derivatives demonstrated potent antiviral activity, with EC 50 values ranging from 0.05 to 1.23 μM in S-Fuse assays against the Omicron variant (BA.2.86.1 lineage) and from 1.4 to 1.53 μM in Calu-3 cells, while showing low cytotoxicity and high selectivity. The most promising compound, 11, predicted by the machine learning-based generative models, exhibited an antiviral potency (EC 50 ) of 1.53 μM in Calu-3 cells infected with the B.1. variant, a CC 50 of 93.9 μM, with a selectivity index of 61.37. Additionally, 11 displayed substantial antiviral activity against various SARS-CoV-2 variants, including against the Omicron variant (BA.2.86.1), with an EC 50 of 0.73 μM in the S-Fuse assay. Furthermore, 11 demonstrated favorable mouse pharmacokinetic properties, including improved aqueous solubility at physiological pH, a prolonged terminal half-life, and increased systemic exposure. Overall, virucidal assays demonstrated that 11 lacks direct virucidal activity, and viral adsorption assays further showed that this compound does not impair viral attachment. Consistent with these findings, exploratory molecular docking results should be regarded as hypothesis-generating, suggesting a potential involvement of compound 11 in later viral entry events rather than in direct viral inactivation. These findings provide a foundation for advancing 11 as a hit compound for further optimization within antiviral strategies against SARS-CoV-2 variants.
Source: ACS Omega
Authors: Melina Mottin, Christopher D. Jurisch, Sabrina Silva-Mendonça, Donald Seanego, Paulo R. P. da Silva Ramos, Caroline S. Freitas, Mayara Mattos, Natalia Fintelman-Rodrigues, Carolina Q. Sacramento, Florence Guivel-Benhassine, Timothée Bruel, Liezl Krugmann, Ana C. Puhl, Fabio Urbina, Thomas R. Lane, Eric M. Merten, Kenneth H. Pearce, Alexander Lepioshkin, Artem Poromov, Natalia Monakhova, Olivier Schwartz, Kelly Chibale, Thiago M. L. Souza, Sean Ekins, Vadim Makarov, Richard K. Gessner, Carolina H. Andrade
Institutions: Universidade de São Paulo, Universidade Federal de Goiás, University of Cape Town, Fundação Oswaldo Cruz, Institut Pasteur, Université Paris Cité, Collaborations Pharmaceuticals (United States), University of North Carolina at Chapel Hill, Russian Academy of Sciences, Federal Research Centre «Fundamentals of Biotechnology» of the Russian Academy of Sciences
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,935
Funders: Nyckelfonden, Support for Pioneering Research Initiated by the Next Generation, Institut des Neurosciences Cliniques de Rennes, Toegepaste en Technische Wetenschappen, NWO, Simons Foundation, World Health Organization, Alexander von Humboldt-Stiftung, Biogen, Small Business Innovation Research, Natural Science Foundation of Shanghai, Villum Fonden, Universidad de Alicante, Henan Normal University, Al Jalila Foundation, Zhoukou Normal University, Arnold Ventures, Chan Zuckerberg Initiative, University of Richmond, Hellenic Academic Libraries Link, Universitätsmedizin Göttingen, European Commission, European Centre for Disease Prevention and Control, University of Bath, South African Medical Research Council, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Natural Science Foundation of China, Technische Universiteit Delft, Academia Sinica, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Austrian Science Fund, Generalitat de Catalunya, China Postdoctoral Science Foundation, Eusko Jaurlaritza, Fonds Wetenschappelijk Onderzoek, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Generalitat Valenciana, Natural Science Foundation of Fujian Province, Science and Technology Commission of Shanghai Municipality, Ministry of Food and Drug Safety, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Korea Health Industry Development Institute, World Institute of Kimchi, Israel Science Foundation, Karolinska Institutet, King Abdulaziz University, Taiwan Semiconductor Manufacturing Company, Centre International de Recherches Médicales de Franceville, Natural Science Foundation of Jiangxi Province, Energimyndigheten, National Research Council of Thailand, Fundação de Amparo à Pesquisa do Estado de Goiás, Universidade Federal de Goiás, United Arab Emirates University, Birla Institute of Technology and Science, Pilani, Russian Science Foundation, Universidad de Castilla-La Mancha, Svenska Läkaresällskapet, Reumatikerförbundet, Shanghai Xuhui District Central Hospital, Education Department of Jiangxi Province, Novo Nordisk Fonden, Putian University, Xunta de Galicia, State Key Laboratory of Chemo/Biosensing and Chemometrics, Junta de Comunidades de Castilla-La Mancha, Priority Academic Program Development of Jiangsu Higher Education Institutions, Higher Education Discipline Innovation Project, China National Nuclear Corporation, Westpac Scholars Trust, Alfaisal University, Brain Tumour Research, Centers for Disease Control and Prevention, U.S. Food and Drug Administration, National Institute of Food and Agriculture, Office of Nuclear Energy, Binghamton University, Animal and Plant Health Inspection Service, University of Colorado Colorado Springs, College of Science, Oregon State University, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Agencia Nacional de Promoción Científica y Tecnológica, College of Medicine and Health Sciences, United Arab Emirates University, European Regional Development Fund, National Key Research and Development Program of China, Project 211, Fundamental Research Funds for the Central Universities, Shanghai Science International Cooperation Project, Key Research and Development Projects of Shaanxi Province, Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Office of Naval Research, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, Division of Materials Research, Division of Electrical, Communications and Cyber Systems, Division of Chemistry, Basic Energy Sciences, National Center for Complementary and Integrative Health, Core Research for Evolutional Science and Technology, Air Force Office of Scientific Research, H2020 European Research Council, Division of Diabetes, Endocrinology, and Metabolic Diseases, HORIZON EUROPE Marie Sklodowska-Curie Actions, HORIZON EUROPE European Research Council, NextGenerationEU
Awards: G1036976577, MegaPredict for predicting natural product uses and their drug interactions, G1384181827, G22113365, MegaTox for analyzing and visualizing data across different screening systems, Centralized assay datasets for modelling support of small drug discovery organizations, G3690646728, G3768531463, G510972860, G5762982347, G6198639042, G8415457339, G8724532333
OpenAlex ID: W7150886502