The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small molecule inhibitors of Ebola virus entry. These 4-(aminomethyl)benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds -). Compounds , , , , and are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (, , and ) have shown good metabolic stability in plasma and liver microsomes (rat and human), and did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671190 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.0c00463 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of Nanosota-EB1 and -EB2 as Novel Nanobody Inhibitors Against Ebola Virus Infection.
PLoS Pathog
December 2024
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
The Ebola filovirus (EBOV) poses a serious threat to global health and national security. Nanobodies, a type of single-domain antibody, have demonstrated promising therapeutic potential. We identified two anti-EBOV nanobodies, Nanosota-EB1 and Nanosota-EB2, which specifically target the EBOV glycoprotein (GP).
View Article and Find Full Text PDFGuardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses.
J Med Chem
December 2024
UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States.
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, -(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (), borne from our previously reported hit-to-lead effort.
View Article and Find Full Text PDFInhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4'-fluorouridine.
Antiviral Res
January 2025
Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077, Göttingen, Germany; Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077, Göttingen, Germany. Electronic address:
Article Synopsis
- - RNA viruses like influenza and coronaviruses pose significant health threats, often lacking effective vaccines or treatments, while others like filo- and henipaviruses have high mortality rates despite limited outbreaks.
- - The antiviral drug 4'-Fluorouridine (4'-FlU) inhibits RNA virus replication by targeting the RNA-dependent RNA polymerase, but its effectiveness varies across different viruses, necessitating strategies to improve its potency.
- - Researchers found that inhibiting dihydroorotate dehydrogenase (DHODH) enhances the antiviral effects of 4'-FlU against several RNA viruses, including in models of infection, potentially by depleting uridine, which boosts 4'-FlU's incorporation into viral
Targeting PRMT7-mediated monomethylation of MAVS enhances antiviral innate immune responses and inhibits RNA virus replication.
Proc Natl Acad Sci U S A
November 2024
State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China.
RIG-I-like receptors (RLRs)-mitochondrial antiviral signaling protein (MAVS) are crucial for type I interferon (IFN) signaling pathway and innate immune responses triggered by RNA viruses. However, the regulatory molecular mechanisms underlying RNA virus-activated type I IFN signaling pathway remain incompletely understood. Here, we found that protein arginine methyltransferase 7 (PRMT7) serves as a negative regulator of the type I IFN signaling pathway by interacting with MAVS and catalyzing monomethylation of arginine 232 (R232me1) in MAVS.
View Article and Find Full Text PDFLipid Selectivity of Membrane Action of the Fragments of Fusion Peptides of Marburg and Ebola Viruses.
Int J Mol Sci
September 2024
Laboratory of Membrane and Ion Channel Modeling, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky 4, 194064 Saint Petersburg, Russia.
The life cycle of Ebola and Marburg viruses includes a step of the virion envelope fusion with the cell membrane. Here, we analyzed whether the fusion of liposome membranes under the action of fragments of fusion peptides of Ebola and Marburg viruses depends on the composition of lipid vesicles. A fluorescence assay and electron microscopy were used to quantify the fusogenic activity of the virus fusion peptides and to identify the lipid determinants affecting membrane merging.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!