Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication

Area of Science:

• Virology
• Drug Discovery
• Structural Biology

Background:

• Pathogenic New World arenaviruses (NWAs) utilize host cell entry mechanisms, presenting targets for antiviral therapies.
• Human transferrin receptor 1 (hTfR1) is a known entry receptor for several NWAs, guiding intervention strategies.

Purpose of the Study:

• To identify small molecules inhibiting NWA infection by targeting the MACV GP1-hTfR1 interaction.
• To develop potent and broadly acting antiviral compounds against pathogenic NWAs.

Main Methods:

• Structure-based virtual screening of drug-like compounds against the MACV GP1-hTfR1 interface.
• Cell-based assays to evaluate antiviral activity against Junín virus (JUNV).
• Hit expansion and analogue synthesis to optimize inhibitory compounds.

Main Results:

• Virtual screening identified 25 candidates, with two scaffolds showing low-micromolar activity against JUNV.
• Hit expansion yielded analogues with submicromolar inhibition of JUNV replication.
• Compound 22f demonstrated broad antiviral activity against hTfR1-tropic NWAs and other NWA strains, with no effect on Rift Valley fever virus.

Conclusions:

• Compound 22f exhibits broad-spectrum antiviral activity against pathogenic NWAs, targeting host-virus entry.
• The identified compounds provide a basis for developing novel therapeutics against NWA infections.
• Further optimization is needed to enhance protection in vivo, as 22f did not confer protection in a mouse model.