Configurationally Locked Ridaifen-B Analogs as Potent Ebola Virus Entry Inhibitors

Area of Science:

• Virology
• Medicinal Chemistry
• Drug Discovery

Background:

• Ebola virus (EBOV) disease presents a significant global health threat due to high mortality and limited treatments.
• The EBOV glycoprotein (GP) is essential for viral entry, making it a key target for antiviral development.

Purpose of the Study:

• To design, synthesize, and evaluate novel cyclized ridaifen-B derivatives as potent inhibitors of EBOV.
• To investigate the antiviral activity and selectivity of these compounds against EBOV and other filoviruses.

Main Methods:

• Synthesis of cyclized ridaifen-B analogs.
• In vitro evaluation of antiviral activity against EBOV and Marburg virus entry.
• Site-directed mutagenesis to identify inhibitor binding sites.
• In vitro pharmacokinetic profiling and in vivo PK studies of a lead compound.

Main Results:

• Several compounds demonstrated nanomolar potency against EBOV GP-mediated entry.
• Submicromolar activity was observed against Marburg virus entry.
• Mutagenesis studies localized inhibitor binding to the EBOV GP1/GP2 fusion loop.
• Hit compound 41 showed favorable in vitro and in vivo pharmacokinetic properties.

Conclusions:

• Cyclized ridaifen-B derivatives represent a promising class of compounds for developing novel antifiloviral agents.
• These compounds, particularly 1,2-dihydronaphthalene and tetrahydronaphthalene derivatives, show potential for targeting EBOV and related filoviruses.
• The identified binding site and favorable PK profile support further development of these inhibitors.