Identification of a pharmacological approach to reduce ACE2 expression and development of an in vitro COVID-19 viral entry model

Yukinori Endo; Brady T. Hickerson; Natalia A. Ilyushina; Nishant Mohan; Hanjing Peng; Kazuyo Takeda; Raymond P. Donnelly; Wen Jin Wu

Journal of Virus Eradication (Dec 2022)

Identification of a pharmacological approach to reduce ACE2 expression and development of an in vitro COVID-19 viral entry model

Yukinori Endo,
Brady T. Hickerson,
Natalia A. Ilyushina,
Nishant Mohan,
Hanjing Peng,
Kazuyo Takeda,
Raymond P. Donnelly,
Wen Jin Wu

Affiliations

Yukinori Endo: Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
Brady T. Hickerson: Division of Biotechnology Review and Research 2 (DBRR2), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
Natalia A. Ilyushina: Division of Biotechnology Review and Research 2 (DBRR2), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
Nishant Mohan: Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
Hanjing Peng: Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
Kazuyo Takeda: Microscopy and Imaging Core Facility, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
Raymond P. Donnelly: Division of Biotechnology Review and Research 2 (DBRR2), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
Wen Jin Wu: Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA; Corresponding author.

Journal volume & issue: Vol. 8, no. 4
p. 100307

Abstract

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Because of rapid emergence and circulation of the SARS-CoV-2 variants, especially Omicron which shows increased transmissibility and resistant to antibodies, there is an urgent need to develop novel therapeutic drugs to treat COVID-19. In this study we developed an in vitro cellular model to explore the regulation of ACE2 expression and its correlation with ACE2-mediated viral entry. We examined ACE2 expression in a variety of human cell lines, some of which are commonly used to study SARS-CoV-2. Using the developed model, we identified a number of inhibitors which reduced ACE2 protein expression. The greatest reduction of ACE2 expression was observed when CK869, an inhibitor of the actin-related protein 2/3 (ARP2/3) complex, was combined with 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), an inhibitor of sodium-hydrogen exchangers (NHEs), after treatment for 24 h. Using pseudotyped lentivirus expressing the SARS-CoV-2 full-length spike protein, we found that ACE2-dependent viral entry was inhibited in CK869 + EIPA-treated Calu-3 and MDA-MB-468 cells. This study provides an in vitro model that can be used for the screening of novel therapeutic candidates that may be warranted for further pre-clinical and clinical studies on COVID-19 countermeasures.

Published in Journal of Virus Eradication

ISSN: 2055-6640 (Print); 2055-6659 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Science: Microbiology; Medicine: Public aspects of medicine
Website: https://www.journals.elsevier.com/journal-of-virus-eradication

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