Dual mechanism: Epigenetic inhibitor apabetalone reduces SARS-CoV-2 Delta and Omicron variant spike binding and attenuates SARS-CoV-2 RNA induced inflammation

by Selleckchem | Jun 02 2023

The SARS-CoV-2 virus initiates infection via interactions between the viral spike protein and the ACE2 receptors on host cells. Variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and transmission. Viral RNAs released after entry into host cells trigger interferon-I (IFN-I) mediated inflammatory responses for viral clearance and resolution of infection. However, overreactive host IFN-I responses and pro-inflammatory signals drive COVID-19 pathophysiology and disease severity during acute infection. These immune abnormalities also lead to the development of post-COVID syndrome if persistent. Novel therapeutics are urgently required to reduce short- and long-term pathologic consequences associated with SARS-CoV-2 infection. Apabetalone, an inhibitor of epigenetic regulators of the BET protein family, is a candidate for COVID-19 treatment via a dual mechanism of action. In vitro, apabetalone downregulates ACE2 gene expression to limit SARS-CoV-2 entry and propagation. In pre-clinical models and patients treated for cardiovascular disease, apabetalone inhibits expression of inflammatory mediators involved in the pathologic cytokine storm (CS) stimulated by various cytokines. Here we show apabetalone treatment of human lung epithelial cells reduces binding of viral spike protein regardless of mutations found in the highly contagious Delta variant and heavily mutated Omicron. Additionally, we demonstrate that apabetalone counters expression of pro-inflammatory factors with roles in CS and IFN-I signaling in lung cells stimulated with SARS-CoV-2 RNA. Our results support clinical evaluation of apabetalone to treat COVID-19 and post-COVID syndrome regardless of the SARS-CoV-2 variant.

Comments：

It appears that the SARS-CoV-2 virus initiates infection through interactions between its spike protein and ACE2 receptors on host cells, and variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and transmission. Viral RNAs released after entry into host cells trigger inflammatory responses mediated by interferon-I (IFN-I) for viral clearance and resolution of infection, but an overactive host immune response can drive COVID-19 pathophysiology and disease severity during acute infection and contribute to the development of post-COVID syndrome.

Apabetalone, an inhibitor of epigenetic regulators of the BET protein family, has been identified as a candidate for COVID-19 treatment due to its dual mechanism of action. In vitro studies have shown that apabetalone downregulates ACE2 gene expression, limiting SARS-CoV-2 entry and propagation. Pre-clinical models and patients treated for cardiovascular disease have demonstrated that apabetalone inhibits expression of inflammatory mediators involved in the pathologic cytokine storm stimulated by various cytokines.

The authors of this passage present results that support the clinical evaluation of apabetalone for the treatment of COVID-19 and post-COVID syndrome, regardless of the SARS-CoV-2 variant. Specifically, they found that apabetalone treatment of human lung epithelial cells reduced binding of viral spike protein, regardless of the mutations found in the highly contagious Delta variant and heavily mutated Omicron. Additionally, apabetalone countered expression of pro-inflammatory factors involved in the cytokine storm and IFN-I signaling in lung cells stimulated with SARS-CoV-2 RNA.