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Optimization of Substrate-Analogue Furin Inhibitors
Teodora Ivanova1, Kornelia Hardes1, Stephanie Kallis2,3
1Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032, Marburg, Germany.
Chemmedchem
|October 24, 2017
Summary
Developing potent and less toxic furin inhibitors is crucial for antiviral drug design. Modifying the structure of a highly potent inhibitor (MI-1148) led to compounds with reduced toxicity and maintained antiviral efficacy.
Area of Science:
- Biochemistry
- Pharmacology
- Virology
Background:
- Furin is a key proprotein convertase involved in viral replication and a target for drug development.
- Existing synthetic furin inhibitors are multibasic, with high potency but narrow therapeutic windows.
- Toxicity of furin inhibitors may correlate with their overall basicity.
Purpose of the Study:
- To develop novel furin inhibitors with improved safety profiles.
- To investigate the structure-toxicity relationship of potent furin inhibitors.
- To identify furin inhibitors with maintained antiviral efficacy against relevant viruses.
Main Methods:
- Chemical modification of a lead furin inhibitor (MI-1148) by altering P1 and P2 residues.
- In vitro enzymatic assays to determine furin inhibition potency.
- Cell-based assays to evaluate antiviral activity against West Nile and Dengue viruses.
- In vivo studies in mice to assess compound toxicity and therapeutic range.
Main Results:
- Replacing the C-terminal benzamidine with less basic residues reduced potency but yielded some low nanomolar inhibitors with negligible cellular efficacy.
- Substituting the P2 arginine with lysine in MI-1148 resulted in a compound with slightly decreased potency but similar antiviral activity and reduced toxicity in mice.
- The modified inhibitor demonstrated comparable efficacy against West Nile and Dengue viruses in cell culture.
Conclusions:
- Reducing the overall basicity of furin inhibitors can decrease toxicity while potentially maintaining antiviral activity.
- Structural modifications, specifically at the P2 position, offer a promising strategy for developing safer and effective furin inhibitors.
- These findings pave the way for the development of well-tolerated antiviral drugs targeting furin-dependent viral infections.
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