Targeting ACE2-RBD interaction as a platform for COVID19 therapeutics: Development and drug repurposing screen of an AlphaLISA proximity assay

Hanson, Quinlin; Wilson, Kelli; Shen, Min; Itkin, Zina; Eastman, Richard T.; Shinn, Paul; Hall, Matthew D.

doi:10.1101/2020.06.16.154708

Cited by 16 publications

(19 citation statements)

References 25 publications

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“…The screening of a small library of compounds using an AlphaLISA-based interaction assay between ACE2 and the RBD domain of the spike protein identified small compounds that displace the interaction. [70] Such kinds of assays can identify small compounds that bind to ACE2 with different mechanisms of action to displace the interaction with spike. Notoriously, one validated "hit" compound that displaced the interaction in vitro was the enalapril (IC 50 7.5 μM), a prodrug approved for the treatment of hypertension that is converted by de-esterification to enaprilat, [70] which is a potent ACE1 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…[70] Such kinds of assays can identify small compounds that bind to ACE2 with different mechanisms of action to displace the interaction with spike. Notoriously, one validated "hit" compound that displaced the interaction in vitro was the enalapril (IC 50 7.5 μM), a prodrug approved for the treatment of hypertension that is converted by de-esterification to enaprilat, [70] which is a potent ACE1 inhibitor. Together with the discussions above, the finding further highlights the possibility that enalapril, at the high concentrations used, might crossreact with ACE2, binding at the active site and allosterically displacing the interaction with the coronavirus spike protein as depicted in Figure 2F.…”

Section: Discussionmentioning

confidence: 99%

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ACE2, the Receptor that Enables Infection by SARS‐CoV‐2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

et al. 2020

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Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID‐19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS‐CoV‐2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full‐length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ACE2, the Receptor that Enables Infection by SARS‐CoV‐2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

et al. 2020

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“…Hanson et. al., have performed a drug repurposing screen against 3384 small molecule drugs using a proximity -based assay which measure the binding of SARS-CoV2 spike protein Domain (RBD) and ACE2, and found 25 high quality small molecule hits that can be evaluated for its efficacy in future ( Hanson et al, 2020 ). Even though druggable pockets are absent in spike protein and ACE2 in their unbound states, bound states have well defined pockets for drug development.…”

Section: Spike Protein-based Therapeuticsmentioning

confidence: 99%

Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development

et al. 2020

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Highlights SARS-CoV-2 binds more strongly to ACE2 as compare to SARS-CoV. The viral Spike protein is most important target for vaccine design. Antibody dependent enhancement enhances the viral entry and replication in the host cell. Nanobody is alternative to avoid Antibody dependent enhancement. Different strategies for vaccine development. Spike protein-based vaccines.

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“…Note that by starting from a different chemical space and not from that of drug-like molecules typically used for HTS, our best SMIs identified here are already well within this low micromolar range for SARS-CoV-2. There also was a recent attempt at identifying possible disruptors of the SARS-CoV-2-S-RBD-ACE2 binding using AlphaLISA assay based HTS of 3,384 small-molecule drugs and pre-clinical compounds suitable for repurposing that identified 25 possible hits (95). However, these were also of relatively low potency (micromolar IC50s).…”

Section: Discussionmentioning

confidence: 99%

Small-MoleculeIn VitroInhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Bojadzic

Garnica

Chen

et al. 2020

Preprint

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Inhibitors of the protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and ACE2, which acts as a ligand-receptor pair that initiates the viral attachment and cellular entry of this coronavirus causing the ongoing COVID-19 pandemic, are of considerable interest as potential antiviral agents. While blockade of such PPIs with small molecules is more challenging than with antibodies, small-molecule inhibitors (SMIs) might offer alternatives that are less strain- and mutation-sensitive, suitable for oral or inhaled administration, and more controllable / less immunogenic. Here, we report the identification of SMIs of this PPI by screening our compound-library that is focused on the chemical space of organic dyes. Among promising candidates identified, several dyes (Congo red, direct violet 1, Evans blue) and novel drug-like compounds (DRI-C23041, DRI-C91005) inhibited the interaction of hACE2 with the spike proteins of SARS-CoV-2 as well as SARS-CoV with low micromolar activity in our cell-free ELISA-type assays (IC50s of 0.2-3.0 μM); whereas, control compounds, such as sunset yellow FCF, chloroquine, and suramin, showed no activity. Protein thermal shift assays indicated that the SMIs identified here bind SARS-CoV-2-S and not ACE2. Selected promising compounds inhibited the entry of a SARS-CoV-2-S expressing pseudovirus into ACE2-expressing cells in concentration-dependent manner with low micromolar IC50s (6-30 μM). This provides proof-of-principle evidence for the feasibility of small-molecule inhibition of PPIs critical for coronavirus attachment/entry and serves as a first guide in the search for SMI-based alternative antiviral therapies for the prevention and treatment of diseases caused by coronaviruses in general and COVID-19 in particular.

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Targeting ACE2-RBD interaction as a platform for COVID19 therapeutics: Development and drug repurposing screen of an AlphaLISA proximity assay

Cited by 16 publications

References 25 publications

ACE2, the Receptor that Enables Infection by SARS‐CoV‐2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

ACE2, the Receptor that Enables Infection by SARS‐CoV‐2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development

Small-MoleculeIn VitroInhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

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