☆ 4.7 Article

Discovery of a AHR pelargonidin agonist that counter-regulates Ace2 expression and attenuates ACE2-SARS-CoV-2 interaction

BIOCHEMICAL PHARMACOLOGY (2021)

Journal

BIOCHEMICAL PHARMACOLOGY

Volume 188, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.bcp.2021.114564

Keywords

Pelargonidin; Intestinal inflammation; TNF-alpha; Ahr; ACE2; NF-kB; SARS-CoV-2

Funding

Italian MIUR/PRIN 2017 [2017FJZZRC]

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Abstract

The study found that pelargonidin can reverse intestinal inflammation by activating the Aryl hydrocarbon Receptor, reducing ACE2 induction. This has potential implications for combating SARS-CoV-2.

The severe acute respiratory syndrome (SARS)-CoV-2 is the pathogenetic agent of Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE)2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV-2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of Ace2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin activates the Aryl hydrocarbon Receptor (AHR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent TNBS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of Ace2 mRNA expression. Colon levels of Ace2 mRNA were directly correlated with Tnf-alpha mRNA levels. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV-2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV-2 Spike protein to ACE2 and reduces the SARS-CoV-2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner.

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p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics)

Daniela Milani, Lorenzo Caruso, Enrico Zauli, Adi Mohammed Al Owaifeer, Paola Secchiero, Giorgio Zauli, Donato Gemmati, Veronica Tisato

Summary: SARS-CoV-2 infection affects various organs and tissues, including the upper and lower airways, lungs, gut, olfactory system, and eyes. The virus alters key transcriptional factors and molecules such as p53, NF-kB, and ACE2, which play a role in immune response impairment and the cytokine storm. Host genetics susceptibility is important in the diverse range of clinical phenotypes observed in COVID-19. Understanding the molecular mechanisms by which SARS-CoV-2 modulates gene expression and balance can help develop strategies to counteract severe forms of the infection.

FRONTIERS IN PHARMACOLOGY (2022)