Pyronaridine Protects against SARS-CoV-2 Infection in Mouse

Area of Science:

• Virology
• Drug Discovery
• Immunology

Background:

• Limited small-molecule antiviral options exist for severe acute respiratory coronavirus 2 (SARS-CoV-2).
• Remdesivir, an existing antiviral, was repurposed from Ebola treatment.
• Computational screening identified potential antiviral candidates.

Purpose of the Study:

• To evaluate pyronaridine, a computationally identified molecule, for its antiviral activity against SARS-CoV-2.
• To assess the in vivo efficacy of pyronaridine in a COVID-19 mouse model.
• To investigate the molecular mechanism of pyronaridine's antiviral action.

Main Methods:

• Assessed pyronaridine's inhibition of SARS-CoV-2 replication in A549-ACE2 cells.
• Evaluated in vivo efficacy in K18-hACE transgenic mice infected with SARS-CoV-2.
• Measured viral load, lung pathology, pro-inflammatory cytokines/chemokines, and cell infiltration.
• Determined pyronaridine's inhibitory effect on viral papain-like protease (PL^pro) and main protease (M^pro) in vitro.

Main Results:

• Pyronaridine significantly reduced viral load in the lungs of infected mice.
• Treatment with pyronaridine decreased lung pathology and pro-inflammatory responses.
• Pyronaridine demonstrated in vitro inhibition of SARS-CoV-2 PL^pro (IC₅₀ = 1.8 μM) but not M^pro.
• Structure-activity relationship studies of pyronaridine analogs for PL^pro inhibition were initiated.

Conclusions:

• Pyronaridine exhibits significant antiviral efficacy against SARS-CoV-2 in vivo.
• The inhibition of viral PL^pro activity represents a potential mechanism for pyronaridine's therapeutic effect.
• Pyronaridine is a promising therapeutic candidate for COVID-19 treatment.