New potent EV-A71 antivirals targeting capsid

Area of Science:

• Virology
• Medicinal Chemistry
• Drug Discovery

Background:

• Enteroviruses are diverse RNA viruses causing numerous diseases, with some infections leading to severe complications, especially in vulnerable populations.
• Current treatments for enteroviruses are limited, with only vaccines available for poliovirus and EV-A71.
• Recent outbreaks highlight the urgent need for broad-spectrum antiviral therapies against enteroviruses.

Purpose of the Study:

• To identify and characterize novel small-molecule inhibitors with broad-spectrum anti-enterovirus activity.
• To evaluate the efficacy and selectivity of these compounds against enterovirus infections.
• To elucidate the binding mechanism of these inhibitors within the viral capsid.

Main Methods:

• Identification of a new class of small-molecule inhibitors targeting the hydrophobic pocket of the enterovirus capsid.
• In vitro evaluation of antiviral activity (EC50) and cytotoxicity (CC50) in cell lines (MRC-5 and RD).
• Analysis of the binding mode of the inhibitors in complex with enterovirus capsids using structural methods.

Main Results:

• The identified compounds demonstrated micromolar activity against EV-A71.
• Compound 6c exhibited potent antiviral activity (EC50 = 0.29 μM in MRC-5 cells) with a high selectivity index (SI > 69).
• Structural analysis revealed conserved interactions between the inhibitors and the viral capsid, suggesting a consistent binding mechanism.

Conclusions:

• A novel class of small-molecule inhibitors targeting the enterovirus capsid has been identified.
• Compound 6c and its derivatives show significant potential as broad-spectrum therapeutic agents against enterovirus infections.
• Further development of these compounds could address the unmet medical need for effective enterovirus treatments.