1. N-Substituted Pyrrole-Based Heterocycles as Broad-Spectrum Filoviral Entry Inhibitors.
- Author
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Durante D, Bott R, Cooper L, Owen C, Morsheimer KM, Patten JJ, Zielinski C, Peet NP, Davey RA, Gaisina IN, Rong L, and Moore TW
- Subjects
- Humans, Structure-Activity Relationship, Heterocyclic Compounds pharmacology, Heterocyclic Compounds chemistry, Heterocyclic Compounds chemical synthesis, Filoviridae drug effects, Marburgvirus drug effects, Pyrroles pharmacology, Pyrroles chemistry, Pyrroles chemical synthesis, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents chemical synthesis, Ebolavirus drug effects, Virus Internalization drug effects
- Abstract
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.
- Published
- 2024
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