Fragment-Based Design, Synthesis, and Characterization of Aminoisoindole-Derived Furin Inhibitors

Area of Science:

• Biochemistry
• Structural Biology
• Virology

Background:

• Proprotein convertase furin is a key target for antiviral drug development.
• Benzamidine-derived inhibitors are known furin inhibitors, but novel P1 groups are sought for improved efficacy.

Purpose of the Study:

• To identify and characterize a new P1 group for synthesizing potent substrate-analogue furin inhibitors.
• To evaluate the antiviral activity of novel furin inhibitors against respiratory syncytial virus (RSV) and influenza A virus.

Main Methods:

• Crystallographic screening of fragments to identify suitable P1 groups for furin.
• Synthesis and characterization of novel peptidic furin inhibitors.
• Antiviral assays in A549 cells to assess inhibition of RSV and influenza A virus replication.
• Structural analysis of inhibitor-furin complexes.

Main Results:

• A 1H-isoindol-3-amine was identified as an effective P1 group for furin inhibition.
• Novel inhibitors exhibited improved picomolar inhibitory potency compared to benzamidine analogues.
• Inhibitors demonstrated efficient antiviral activity against RSV and influenza A virus at low micromolar concentrations.
• Crystal structures confirmed the suitability of the new P1 group for peptidic inhibitor design.

Conclusions:

• The novel 1H-isoindol-3-amine P1 group is well-suited for developing potent furin inhibitors.
• These inhibitors show promise as antiviral agents against RSV and influenza.
• Potential off-target effects on Mas-related G-protein coupled receptor GPCR-X2 were noted for some benzamidine derivatives.