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Published on: September 27, 2014
Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses
Malaika D Argade1,2, Jazmin Galván Achi3, Ryan Bott3
1UICentre: Drug Discovery, University of Illinois Chicago, Chicago, Illinois 60612, United States.
Abstract:
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.
Insights
Researchers optimized a lead compound to develop new small molecule therapeutics for Ebola virus (EBOV) and Marburg virus (MARV) infections. Optimized analogs show promising antiviral activity and drug-like properties for further studies.
Area of Science:
- Virology and Drug Discovery
- Medicinal Chemistry
- Infectious Diseases
Background:
- Ebola virus (EBOV) and Marburg virus (MARV) cause fatal hemorrhagic fevers with significant outbreak history.
- No FDA-approved small molecule therapeutics currently exist for filoviral diseases, representing a critical unmet medical need.
Purpose of the Study:
- To systematically optimize an early lead compound (compound 1) for enhanced antiviral activity against EBOV and MARV.
- To identify novel small molecule therapeutics with improved efficacy and druglike properties for filoviral infections.
Main Methods:
- Conducted a secondary structure-activity relationship (SAR) study involving deconstruction and reconstruction of compound 1.
- Synthesized and tested novel analogs against pseudotyped EBOV and MARV.
- Validated antiviral activity in infectious assays and assessed off-target effects and druglike properties.
Main Results:
- Optimized analogs demonstrated significant antiviral activity against various ebolaviruses.
- Reduced off-target activity was observed in the most promising lead compounds.
- Selected analogs exhibited favorable druglike properties suitable for further preclinical development.
Conclusions:
- Systematic structural optimization yielded potent small molecule candidates for EBOV and MARV.
- The identified compounds represent promising leads for in vivo efficacy studies in the ongoing drug discovery campaign.
- This work addresses the critical need for effective therapeutics against filoviral hemorrhagic fevers.
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