Targeting ACE2 for COVID-19 Therapy: Opportunities and Challenges

Jia, Hongpeng; Neptune, Enid; Cui, Honggang

doi:10.1165/rcmb.2020-0322ps

Cited by 83 publications

(80 citation statements)

References 90 publications

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“…Taken together, these findings suggest that zinc supplementation may augment the inhibitory effect of triclabendazole and emetine on ACE2 expression. Given that ACE2 has multiple physiological roles in regulating cardiovascular, renal and innate immune systems, targeting ACE2 for disease treatment requires careful consideration of the potential positive and negative effects on the patient [32] .…”

Section: Discussionmentioning

confidence: 99%

Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines

et al. 2021

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Aims Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2. Main methods Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-κB inhibitor treatment. Surface ACE2 expression and intracellular reactive oxygen species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay. Key findings Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N -acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-κB inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells. Significance These results suggest that ACE2 expression is modulated by ROS and NF-κB signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.

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Section: Discussionmentioning

confidence: 99%

Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines

et al. 2021

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“…Besides vaccination against COVID-19, blocking the accessibility of the virus to membranebound ACE2 as the primary receptor for SARS-CoV-2 target cell entry, represents an alternative strategy to prevent COVID-19. Here, different approaches exist (19), but of course each of these treatment strategies also has its fundamental as well as translational challenges which need to be overcome for clinical utility. Technical hurdles include off-target potential, ACE2-independent effects, stability or toxicity (19).…”

Section: Discussionmentioning

confidence: 99%

“…Here, different approaches exist (19), but of course each of these treatment strategies also has its fundamental as well as translational challenges which need to be overcome for clinical utility. Technical hurdles include off-target potential, ACE2-independent effects, stability or toxicity (19). Compounds from natural origin could be an important resource here as they are described long term and many of them have been established as safe.…”

Section: Discussionmentioning

confidence: 99%

“…The development of effective prevention and treatment strategies for SARS-CoV-2 infection is still at the early stages. Although the first vaccines received now marketing authorization, challenges in distribution concerns or about durable effectiveness, and risk of re-infection remain (17, 18). Subsequent infections may possibly be milder than the first one, though.…”

Section: Discussionmentioning

confidence: 99%

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Common dandelion (Taraxacum officinale) efficiently blocks the interaction between ACE2 cell surface receptor and SARS-CoV-2 spike protein D614, mutants D614G, N501Y, K417N and E484Kin vitro

Tran

Npk

Gigl

et al. 2021

Preprint

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On 11th March 2020, coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, was declared as a global pandemic by the World Health Organization (WHO). To date, there are rapidly spreading new “variants of concern” of SARS-CoV-2, the United Kingdom (B.1.1.7), the South African (B.1.351) or Brasilian (P.1) variant. All of them contain multiple mutations in the ACE2 receptor recognition site of the spike protein, compared to the original Wuhan sequence, which is of great concern, because of their potential for immune escape. Here we report on the efficacy of common dandelion (Taraxacum officinale) to block protein-protein interaction of spike S1 to the human ACE2 cell surface receptor. This could be shown for the original spike D614, but also for its mutant forms (D614G, N501Y, and mix of K417N, E484K, N501Y) in human HEK293-hACE2 kidney and A549-hACE2-TMPRSS2 lung cells. High molecular weight compounds in the water-based extract account for this effect. Infection of the lung cells using SARS-CoV-2 spike pseudotyped lentivirus particles was efficiently prevented by the extract and so was virus-triggered pro-inflammatory interleukin 6 secretion. Modern herbal monographs consider the usage of this medicinal plant as safe. Thus, the in vitro results reported here should encourage further research on the clinical relevance and applicability of the extract as prevention strategy for SARS-CoV-2 infection.Significance statementSARS-CoV-2 is steadily mutating during continuous transmission among humans. This might eventually lead the virus into evading existing therapeutic and prophylactic approaches aimed at the viral spike. We found effective inhibition of protein-protein interaction between the human virus cell entry receptor ACE2 and SARS-CoV-2 spike, including five relevant mutations, by water-based common dandelion (Taraxacum officinale) extracts. This was shown in vitro using human kidney (HEK293) and lung (A549) cells, overexpressing the ACE2 and ACE2/TMPRSS2 protein, respectively. Infection of the lung cells using SARS-CoV-2 pseudotyped lentivirus was efficiently prevented by the extract. The results deserve more in-depth analysis of dandelions’ effectiveness in SARS-CoV-2 prevention and now require confirmatory clinical evidence.

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“…Therefore, targeting the Spike-ACE2 binding event has been logically viewed as a promising strategy to mitigate viral infection and control the infection. To date, decoy ACE2 soluble protein (6), ACE2 inhibitor and TMPRSS2 inhibitor (4) had been investigated for trapping the virus and blocking the binding of spike protein for reducing the accessibility of the virus to host cells (7). Their clinical efficacy and safety for COVID-19 patients are still exploring.…”

Section: Introductionmentioning

confidence: 99%

Zinc supplement augments the suppressive effects of repurposed drugs of NF-kappa B inhibitor on ACE2 expression in human lung cell lines in vitro

Lee

Chen

Hsu

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a vast number of infections and fatalities worldwide. As the development and safety validation of effective vaccines are ongoing, drug repurposing is most efficient approach to search FDA approved agents against coronavirus disease 2019 (COVID-19). In the present study, we found that endogenous ACE2 expressions could be detected in H322M and Calu-3 cell lines, as well as their ACE2 mRNA and protein expressions were suppressed by pyrrolidine dithiocarbamate (PDTC), a NF-kappa B inhibitor, in dose- and time-dependent manners. Moreover, N-acetyl-cysteine (NAC) pretreatment reversed PDTC-induced ACE2 suppression, as well as the combined treatment of hydrogen peroxide and knockdown of p50 subunit of NF-kappa B by siRNA reduced ACE2 expression in H322M cells. In addition, anthelmintic drug triclabendazole and antiprotozoal drug emetine, repurposed drugs of NF-kappa B inhibitor, also inhibited ACE2 mRNA and protein expressions in H322M cells. Moreover, zinc supplement augmented the suppressive effects of triclabendazole and emetine on ACE2 suppression in H322M and Calu-3 cells. Taken together, these results indicate that ACE2 expression is modulated by reactive oxygen species (ROS) and NF-kappa B signal in human lung cell lines, and zinc combination with triclabendazole or emetine has the clinical potential for the prevention and treatment of COVID-19.

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Targeting ACE2 for COVID-19 Therapy: Opportunities and Challenges

Cited by 83 publications

References 90 publications

Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines

Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines

Common dandelion (Taraxacum officinale) efficiently blocks the interaction between ACE2 cell surface receptor and SARS-CoV-2 spike protein D614, mutants D614G, N501Y, K417N and E484Kin vitro

Zinc supplement augments the suppressive effects of repurposed drugs of NF-kappa B inhibitor on ACE2 expression in human lung cell lines in vitro

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