Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Area of Science:

• Virology
• Medicinal Chemistry
• Molecular Biology

Background:

• The COVID-19 pandemic highlighted the critical need for novel antiviral drugs against coronaviruses (CoVs).
• Small molecules can act as chemical probes to understand viral replication and as therapeutic leads.

Purpose of the Study:

• To identify and characterize novel small molecules that inhibit coronavirus replication.
• To explore amiloride derivatives as potential antivirals targeting conserved viral RNA structures.

Main Methods:

• Screening of amiloride-based compounds for antiviral activity against OC43 and SARS-CoV-2.
• Nuclear magnetic resonance (NMR) spectroscopy to determine drug-target interactions.
• Retrospective molecular docking studies to predict binding affinity.

Main Results:

• Identification of amiloride derivatives that potently inhibit OC43 and SARS-CoV-2 replication.
• Structural studies revealed specific amiloride binding to stem-loop structures in the viral 5′-untranslated regions.
• Lead amilorides showed strong predicted binding to these conserved RNA elements.

Conclusions:

• Amilorides are the first small molecules demonstrated to target RNA structures in the 5′ untranslated regions of CoV genomes.
• These amiloride compounds serve as valuable chemical probes for CoV RNA biology.
• This work paves the way for developing novel, specific antiviral therapies targeting CoV RNA structures.