Targeting coronaviral inflammation: aptamer-based strategies for emerging threats

Area of Science:

• Biotechnology
• Immunology
• Virology

Background:

• Coronaviruses pose significant global health threats, necessitating novel therapeutic strategies against emerging variants.
• The nucleocapsid (N) protein is a conserved target across multiple coronaviruses, implicated in host inflammatory responses.

Purpose of the Study:

• To engineer a broad-spectrum DNA aptamer targeting the conserved coronavirus nucleocapsid (N) protein.
• To develop and evaluate a novel therapeutic agent for inhibiting coronavirus replication and associated inflammation.

Main Methods:

• Engineered a single-stranded DNA aptamer (NApt8-3) binding to the conserved N protein of various coronaviruses.
• Developed circSASON, a chimera combining NApt8-3, an anti-spike aptamer, and an antisense oligonucleotide (ASO) targeting the N gene.
• Assessed in vitro efficacy against SARS-CoV-2 replication and cytokine expression, and in vivo therapeutic potential via intranasal administration in mice.

Main Results:

• NApt8-3 selectively binds the N protein, inhibiting N protein-induced inflammatory cytokine expression by blocking NLRP3 inflammasome interaction.
• circSASON demonstrated effective inhibition of SARS-CoV-2 replication and suppressed N protein-induced cytokine production in vitro.
• Intranasal administration of circSASON significantly reduced viral load and alleviated pulmonary inflammation in a mouse model of SARS-CoV-2 infection.

Conclusions:

• NApt8-3 is a potent broad-spectrum anti-inflammatory agent targeting the conserved coronavirus N protein.
• The circSASON therapeutic strategy shows promise for combating SARS-CoV-2 and potentially future coronavirus variants.
• This study provides a framework for rapid development of aptamer-based therapeutics against emerging viral threats.