Fuente: Microorganisms - Revista científica (MDPI) Microorganisms, Vol. 13, Pages 2809: Fisetin as an Antiviral Agent Targeting the RNA-Dependent RNA Polymerase of SARS-CoV-2: Computational Prediction and In Vitro Experimental Validation
Microorganisms doi: 10.3390/microorganisms13122809
Authors:
Ximena Hernández-Rodríguez
Flor Itzel Lira-Hernández
José Manuel Reyes-Ruíz
Juan Fidel Osuna-Ramos
Carlos Noe Farfán-Morales
Daniela Nahomi Calderón-Sandate
Julio Enrique Castañeda-Delgado
Moisés León-Juárez
Rosa María del Ángel
Bruno Rivas-Santiago
Saúl Noriega
David Mauricio Cañedo-Figueroa
Sarita Montaño
Alan Orlando Santos-Mena
Ana Cristina García-Herrera
Luis Adrián De Jesús-González

SARS-CoV-2 continues to evolve into immune-evasive variants, and although vaccination remains the cornerstone of prevention, the search for antiviral molecules targeting conserved viral enzymes remains essential. The RNA-dependent RNA polymerase (NSP12) is a central component of coronavirus replication, and natural polyphenols have been recurrently proposed as modulators of viral polymerases. Among these compounds, Fisetin has been reported to interact with multiple viral and cellular pathways, yet its direct antiviral activity against SARS-CoV-2 remained largely unexplored. Here, we first analyzed the interaction of Fisetin with the catalytic and NiRAN domains of NSP12 using molecular docking and molecular dynamics simulations, revealing stable and energetically favorable binding throughout a 100 ns simulation. Previous biochemical reports have shown that Fisetin inhibits the recombinant SARS-CoV-2 RdRp, supporting its potential to engage the polymerase. We then evaluated its antiviral activity in human A549 lung epithelial cells infected with the Omicron JN.1 variant. We observed a clear dose-dependent reduction in viral infection, achieving up to 91.9% inhibition at 3 μM while maintaining acceptable cell viability. In addition, Fisetin displayed a selectivity index superior to that of Lopinavir, the positive antiviral control used in this study. Altogether, our findings demonstrate that Fisetin possesses reproducible antiviral activity in a physiologically relevant human lung model and support its role as a natural scaffold for the rational development of polymerase-targeting antivirals against emerging SARS-CoV-2 variants.