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Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications

Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Academic Editor: Ugo Moens
Int. J. Mol. Sci. 2021, 22(20), 10963; https://doi.org/10.3390/ijms222010963
Received: 30 August 2021 / Revised: 7 October 2021 / Accepted: 9 October 2021 / Published: 11 October 2021
(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)
SARS-CoV-2 exploits the respiratory tract epithelium including lungs as the primary entry point and reaches other organs through hematogenous expansion, consequently causing multiorgan injury. Viral E protein interacts with cell junction-associated proteins PALS1 or ZO-1 to gain massive penetration by disrupting the inter-epithelial barrier. Conversely, receptor-mediated viral invasion ensures limited but targeted infections in multiple organs. The ACE2 receptor represents the major virion loading site by virtue of its wide tissue distribution as demonstrated in highly susceptible lung, intestine, and kidney. In brain, NRP1 mediates viral endocytosis in a similar manner to ACE2. Prominently, PDZ interaction involves the entire viral loading process either outside or inside the host cells, whereas E, ACE2, and NRP1 provide the PDZ binding motif required for interacting with PDZ domain-containing proteins PALS1, ZO-1, and NHERF1, respectively. Hijacking NHERF1 and β-arrestin by virion loading may impair specific sensory GPCR signalosome assembling and cause disordered cellular responses such as loss of smell and taste. PDZ interaction enhances SARS-CoV-2 invasion by supporting viral receptor membrane residence, implying that the disruption of these interactions could diminish SARS-CoV-2 infections and be another therapeutic strategy against COVID-19 along with antibody therapy. GPCR-targeted drugs are likely to alleviate pathogenic symptoms-associated with SARS-CoV-2 infection. View Full-Text
Keywords: SARS-CoV-2; PDZ interaction; viral cell entry; GPCR signaling; drug development SARS-CoV-2; PDZ interaction; viral cell entry; GPCR signaling; drug development
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MDPI and ACS Style

Zhang, Q.; Friedman, P.A. Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications. Int. J. Mol. Sci. 2021, 22, 10963. https://doi.org/10.3390/ijms222010963

AMA Style

Zhang Q, Friedman PA. Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications. International Journal of Molecular Sciences. 2021; 22(20):10963. https://doi.org/10.3390/ijms222010963

Chicago/Turabian Style

Zhang, Qiangmin, and Peter A. Friedman. 2021. "Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications" International Journal of Molecular Sciences 22, no. 20: 10963. https://doi.org/10.3390/ijms222010963

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