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BRIEF RESEARCH REPORT article

Front. Drug Discov.
Sec. Technologies and Strategies to Enable Drug Discovery
Volume 4 - 2024 | doi: 10.3389/fddsv.2024.1416728

Brief Research Report: Transcriptional blockade of angiotensin converting enzyme 2 modelled in human retinal pigment epithelial cells

Provisionally accepted
Liam M. Ashander Liam M. Ashander 1Amanda L. Lumsden Amanda L. Lumsden 1Yuefang Ma Yuefang Ma 1Alwin C. Tan Alwin C. Tan 1Binoy Appukuttan Binoy Appukuttan 1Santhosh Daniel Santhosh Daniel 1,2Michael Z. Michael Michael Z. Michael 1,2Justine R. Smith Justine R. Smith 1,2*
  • 1 Flinders University, Adelaide, South Australia, Australia
  • 2 Flinders Medical Centre, Bedford Park, South Australia, Australia

The final, formatted version of the article will be published soon.

    As a key host protein involved in cellular infection by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), angiotensin converting enzyme (ACE)2 is an ideal target for antiviral drugs. Manipulation of transcription provides opportunity for graduated blockade that preserves physiological functions. We sought to develop a model system for evaluating manipulation of ACE2 gene transcription using human retinal pigment epithelium. Retinal pigment epithelial cell isolates were prepared from human posterior eyecups (n = 11 individual isolates). The cells expressed ACE2 transcript and protein, and expression was not induced by hypoxia mimetic dimethyloxaloylglycine, or inflammatory cytokine IL-1β. ACE2 gene transcription factors were predicted in silico and crossreferenced with the human retinal pigment epithelial cell transcriptome, and 5 candidate transcription factors were identified: ETS proto-oncogene 1 transcription factor (ETS1), nuclear factor I C (NFIC), nuclear receptor subfamily 2 group C member 1 (NR2C1), TEA domain transcription factor 1 (TEAD1), and zinc finger protein 384 (ZNF384). The candidates were individually targeted in cells by transfection with small interfering (si)RNA. Knockdowns reduced mean cellular expression of all the transcription factors in comparison to expression in cells transfected with control non-targeted siRNA. Mean cellular ACE2 transcript was reduced under the condition of NR2C1 knockdown, but not for ETS1, NFIC, TEAD1, and ZNF384 knockdowns. Our findings build on previous work demonstrating the potential for drugging gene transcription. Importantly, we show the value of human retinal pigment epithelium as a system for evaluating ACE2 transcriptional blockade, a possible approach for treating SARS-CoV-2 infection.

    Keywords: transcription, ACE2, Nr2c1, Retinal Pigment Epithelium, Drugging

    Received: 13 Apr 2024; Accepted: 29 Aug 2024.

    Copyright: © 2024 Ashander, Lumsden, Ma, Tan, Appukuttan, Daniel, Michael and Smith. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Justine R. Smith, Flinders University, Adelaide, 5042, South Australia, Australia

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.