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CNP blocks mitochondrial depolarization and inhibits SARS-CoV-2 replication in vitro and in vivo
James Logue1,2, Victoria M Melville1,2, Jeremy Ardanuy1,2
1The Department of Microbiology and Immunology, The University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Abstract:
The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world's healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus replication cycle have been developed however, effective late-stage therapeutical targets have yet to be identified. To that end, our lab identified that 2',3' cyclic-nucleotide 3'-phosphodiesterase (CNP) inhibits SARS-CoV-2 virion assembly. We show that CNP inhibits the generation of new SARS-CoV-2 virions, reducing intracellular titers without inhibiting viral structural protein translation. Additionally, we show that targeting of CNP to mitochondria is necessary for inhibition, blocking mitochondrial depolarization and implicating CNP's proposed role as an inhibitor of the mitochondrial permeabilization transition pore (mPTP) as the mechanism of virion assembly inhibition. We also demonstrate that an adenovirus expressing virus expressing both human ACE2 and CNP inhibits SARS-CoV-2 titers to undetectable levels in lungs of mice. Collectively, this work shows the potential of CNP to be a new SARS-CoV-2 antiviral target.
Insights
Researchers discovered that 2
Area of Science:
- Virology
- Biochemistry
- Molecular Biology
Background:
- The COVID-19 pandemic has caused significant global health and economic disruption.
- Existing therapeutics primarily target early viral replication stages, leaving a need for late-stage intervention targets.
- Identifying novel targets for SARS-CoV-2 is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP) in SARS-CoV-2 replication.
- To determine if CNP can serve as a therapeutic target for inhibiting viral assembly.
- To elucidate the mechanism by which CNP affects viral production.
Main Methods:
- Assessed the impact of CNP on SARS-CoV-2 virion assembly and intracellular titers.
- Investigated the necessity of CNP mitochondrial targeting for antiviral activity.
- Examined the effect of CNP on mitochondrial depolarization and the mitochondrial permeabilization transition pore (mPTP).
- Utilized an adenovirus expressing human ACE2 and CNP in a mouse model to evaluate in vivo efficacy.
Main Results:
- CNP was found to inhibit SARS-CoV-2 virion assembly, reducing viral titers without affecting viral protein translation.
- Targeting CNP to mitochondria was essential for its antiviral effect, preventing mitochondrial depolarization.
- CNP's mechanism involves inhibiting the mPTP, thereby blocking viral assembly.
- Adenovirus-mediated expression of CNP significantly reduced SARS-CoV-2 levels in mouse lungs.
Conclusions:
- 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP) is a novel inhibitor of SARS-CoV-2 virion assembly.
- CNP's antiviral activity is mediated through its interaction with mitochondria and the mPTP.
- CNP represents a promising new therapeutic target for developing late-stage antiviral strategies against SARS-CoV-2.
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