Angiotensin-Converting Enzyme 2-Based Biosensing Modalities and Devices for Coronavirus Detection

Abstract

Rapid and cost-effective diagnostic tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a critical and valuable weapon for the coronavirus disease 2019 (COVID-19) pandemic response. SARS-CoV-2 invasion is primarily mediated by human angiotensin-converting enzyme 2 (hACE2). Recent developments in ACE2-based SARS-CoV-2 detection modalities accentuate the potential of this natural host-virus interaction for developing point-of-care (POC) COVID-19 diagnostic systems. Although research on harnessing ACE2 for SARS-CoV-2 detection is in its infancy, some interesting biosensing devices have been developed, showing the commercial viability of this intriguing new approach. The exquisite performance of the reported ACE2-based COVID-19 biosensors provides opportunities for researchers to develop rapid detection tools suitable for virus detection at points of entry, workplaces, or congregate scenarios in order to effectively implement pandemic control and management plans. However, to be considered as an emerging approach, the rationale for ACE2-based biosensing needs to be critically and comprehensively surveyed and discussed. Herein, we review the recent status of ACE2-based detection methods, the signal transduction principles in ACE2 biosensors and the development trend in the future. We discuss the challenges to development of ACE2-biosensors and delineate prospects for their use, along with recommended solutions and suggestions.

Keywords: ACE2 biosensors; COVID-19; SARS-CoV-2; colorimetric sensors; electrochemical detection; low-cost diagnostic.

Figure 1

Schematic illustration of SARS-CoV-2 detection systems. Created with Biorender.

Figure 2

ACE2 gene domain organization and protein structure. (A), Full-length ACE2 containing a signal peptide (SP), an N-terminal peptidase domain (PD), and a C-terminal collectrin-like domain (CLD). (B), Protein structure of full-length ACE2 dimer in complex with B°AT1 (PDB ID: PDB 6M17). B°AT1 is presented in grey and four key sites (1–4) are highlighted. The numbers (1–805) indicate the amino acid residues. Adapted from Ref. [31] with permission from the publisher. ^© 2020 Wiley-VCH GmbH.

Figure 3

AFM study of ACE2-S- protein binding mechanism. (A), Components of the virus particle. (B), Complex between receptor-binding domain (RBD) of SARS-CoV-2 and ACE2. (C), Atomic force microscopy (AFM) study of the ACE2 binding with RBD. The ACE2 receptor is immobilized on a surface and S1 subunit or RBD is attached to the surface of the AFM tip. Adaptede from Ref. [39] with permission from the author. “This article is licensed under a Creative Commons Attribution 4.0 International License”. http://creativecommons.org/licenses/by/4.0/ (accessed on 25 October 2022).

Figure 4

ACE2-based biosensing systems for detection of SARS-CoV-2 [51,52,53,54] Created with Biorender.

Figure 5

SARS-CoV-2 detection by RAPID test. (A), Working principle of RAPID test. (B), Functionalization of working electrode. (C), Comparison of RAPID test with some FDA-approved tests. Reprinted from Ref. [51] with permission from Elsevier. ^© 2021 Elsevier Inc.

Figure 6

Characterization of the functionalized electrode and development of calibration curve. (A), Workflow of the method. (B), Cyclic voltammetry (CV) plots of different functionalization steps showing change in current with addition of functionalization layers. (C), Nyquist plots of different functionalization steps showing change in charge transfer resistance (R_CT) with each functionalization step. (D), Nyquist plots for varying concentration of spike protein in saliva of a healthy donor. While E shows sensor response to varying concentrations of inactivated virus. Insets in D and (E) show linear range of the system. Responses after functionalization with glutaraldehyde, ACE2, BSA, and Nafion are shown in red, blue, green, and purple, respectively, while response of bare electrode is shown in black. Reprinted from Ref. [51] with permission from Elsevier. ^© 2021 Elsevier Inc.

Figure 7

Schematic representation of the fabrication of PFDT-ACE2 biosensor. Top portion shows the sensor fabrication procedure and bottom part shows sensor signals obtained using electrochemical impedance spectroscopy. PFDT, 1H1H,2H,2H-Perfluorodecanethiol; R_ct: Charge transfer resistance. Adapted from Ref. [65] with permission from the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. https://creativecommons.org/licenses/by/3.0/ (accessed on 21 October 2022).

Figure 8

Schematic illustration of the biosensor fabrication and detection principle. (A), Electrode system of the developed sensor. (B), Functionalization of working electrode. (C), Detection principle. RE, reference electrode; WE, working electrode; CE, counter electrode. Adapted from Ref. [52] with permission from authors. Copyright © 2021, the authors. This article is licensed under a Creative Commons Attribution license 4.0 (CC BY) https://creativecommons.org/licenses/by/4.0/ (accessed on 21 October 2022).

Figure 9

Lateral flow assay-based SARS-CoV-2 detection. (A), The cellular receptor of the SARS-CoV-2, the ACE2 expressed on lung epithelial cells. (B), Schematic of the LFIA for SARS-CoV-2 detection. Adapted from Ref. [53] with permission from Elsevier. ^© 2020 Published by Elsevier B.V.

Figure 10

Schematic of SERS biosensor based on ACE2 for SARS-CoV-2 detection. Adapted from Ref. [54] with permission from authors. Copyright © 2021, the authors. This article is licensed under a Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ (accessed on 12 October 2022).

Figure 11

Schematic representation of the antifouling COVID-19 sensor. PANI, polyaniline; SA, streptavidin; GCE, glassy carbon electrode. Adapted from Ref. [155] with permission from the American Chemical Society. ^© 2021, American Chemical Society.

Figure 12

Schematic representation of the IoMT system.