N-Substituted Pyrrole-Based Heterocycles as Broad-Spectrum Filoviral Entry Inhibitors.
Destiny Durante, Ryan Bott, Laura Cooper, Callum Owen, Kimberly M Morsheimer, J J Patten, Christian Zielinski, Norton P Peet, Robert A Davey, Irina N Gaisina, Lijun Rong, Terry W Moore
Author Information
Destiny Durante: Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States. ORCID
Ryan Bott: Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60612, United States.
Laura Cooper: Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60612, United States.
Callum Owen: Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States.
Kimberly M Morsheimer: Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States. ORCID
J J Patten: Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States. ORCID
Christian Zielinski: UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States.
Norton P Peet: Chicago BioSolutions Inc., Chicago, Illinois 60612, United States.
Robert A Davey: Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States. ORCID
Irina N Gaisina: Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States. ORCID
Lijun Rong: Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60612, United States.
Terry W Moore: Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States. ORCID
Since the largest and most fatal Ebola virus epidemic during 2014-2016, there have been several consecutive filoviral outbreaks in recent years, including those in 2021, 2022, and 2023. Ongoing outbreak prevalence and limited FDA-approved filoviral therapeutics emphasize the need for novel small molecule treatments. Here, we showcase the structure-activity relationship development of N-substituted pyrrole-based heterocycles and their potent, submicromolar entry inhibition against diverse filoviruses in a target-based pseudovirus assay. Inhibitor antiviral activity was validated using replication-competent Ebola, Sudan, and Marburg viruses. Mutational analysis was used to map the targeted region within the Ebola virus glycoprotein. Antiviral counter-screen and phospholipidosis assays were performed to demonstrate the reduced off-target activity of these filoviral entry inhibitors. Favorable antiviral potency, selectivity, and drug-like properties of the N-substituted pyrrole-based heterocycles support their potential as broad-spectrum antifiloviral treatments.
