N-Substituted Pyrrole-Based Heterocycles as Broad-Spectrum Filoviral Entry Inhibitors.

Autor:	Durante D; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States., Bott R; Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60612, United States., Cooper L; Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60612, United States., Owen C; Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States., Morsheimer KM; Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States., Patten JJ; Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States., Zielinski C; UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States., Peet NP; Chicago BioSolutions Inc., Chicago, Illinois 60612, United States., Davey RA; Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States., Gaisina IN; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States.; Chicago BioSolutions Inc., Chicago, Illinois 60612, United States.; UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States., Rong L; Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60612, United States.; Chicago BioSolutions Inc., Chicago, Illinois 60612, United States., Moore TW; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States.; University of Illinois Cancer Center, University of Illinois Chicago, Chicago, Illinois 60612, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Aug 22; Vol. 67 (16), pp. 13737-13764. Date of Electronic Publication: 2024 Aug 06.
DOI:	10.1021/acs.jmedchem.4c00527
Abstrakt:	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.
Databáze:	MEDLINE
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