Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses.

Autor:	Argade MD; UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States.; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States., Achi JG; Department of Microbiology and Immunology, 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., Morsheimer KM; Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States., Owen CD; Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States., Zielinski CA; UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States.; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States., Gaisin AM; UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States.; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States., Alvarez M; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States., Moore TW; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States., Bu F; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, United States.; Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota 55455, United States., Li F; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, United States.; Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota 55455, United States., Cameron M; Department of Molecular Medicine, Herbert Wertheim, UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida 33458, United States., Anantpadma M; The Integrated Research Facility, National Institute of Allergy and Infectious Diseases, Frederick, Maryland 20892, United States., Davey RA; Department of Virology, Immunology, and Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Medical Campus, Boston, Massachusetts 02118, United States., Peet NP; Chicago BioSolutions Inc., 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., Gaisina IN; UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States.; Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, Illinois 60612, United States.; Chicago BioSolutions Inc., Chicago, Illinois 60612, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Dec 16. Date of Electronic Publication: 2024 Dec 16.
DOI:	10.1021/acs.jmedchem.4c01646
Abstrakt:	Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, N -(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide ( 1 ), borne from our previously reported hit-to-lead effort. This secondary round of structure-activity relationship (SAR) involved the design and synthesis of several deconstructed and reconstructed analogs of compound 1 , which were then tested against pseudotyped EBOV and MARV. The antiviral activities of the most promising leads were further validated in infectious assays. The optimized analogs exhibited desirable antiviral activity against different ebolaviruses and reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates for in vivo efficacy studies as part of our ongoing drug discovery campaign against EBOV and MARV.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu