Project description:Targeting the interaction between the spike protein receptor binding domain (S-RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2) is a potential therapeutic strategy for treating coronavirus disease 2019 (COVID-19). However, we still lack small-molecule drug candidates for this target due to the missing knowledge in the hot spots for the protein-protein interaction. Here, we used NanoBiT technology to identify three Ginkgolic acids from an in-house traditional Chinese medicine (TCM) library, and they interfere with the S-RBD/ACE2 interplay. Our pseudovirus assay showed that one of the compounds, Ginkgolic acid C17:1 (GA171), significantly inhibits the entry of original SARS-CoV-2 and its variants into the ACE2-overexpressed HEK293T cells. We investigated and proposed the binding sites of GA171 on S-RBD by combining molecular docking and molecular dynamics simulations. Site-directed mutagenesis and surface plasmon resonance revealed that GA171 specifically binds to the pocket near R403 and Y505, critical residues of S-RBD for S-RBD interacting with ACE2. Thus, we provide structural insights into developing new small-molecule inhibitors and vaccines against the proposed S-RBD binding site.

| S-EPMC9743696 | biostudies-literature

Identification and characterization of a monoclonal antibody blocking the SARS-CoV-2 spike protein-ACE2 interaction.

Project description: Not available

| S-EPMC8100359 | biostudies-literature

mouse ACE2 receptor bound to SARS-CoV-2 variant Beta Spike

Project description: Not available

| EMPIAR-11181 | biostudies-other

Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

Project description: Not available

| S-BSST649 | biostudies-other

A novel screening strategy of anti-SARS-CoV-2 drugs via blocking interaction between Spike RBD and ACE2.

Project description:Corona virus disease 2019 has spread worldwide, and appropriate drug design and screening activities are required to overcome the associated pandemic. Using computational simulation, blockade mechanism of SARS-CoV-2 spike receptor binding domain (S RBD) and human angiotensin converting enzyme 2 (hACE2) was clarified based on interactions between RBD and hesperidin. Interactions between anti-SARS-CoV-2 drugs and therapy were investigated based on the binding energy and druggability of the compounds, and they exhibited negative correlations; the compounds were classified into eight common types of structures with highest activity. An anti-SARS-CoV-2 drug screening strategy based on blocking S RBD/hACE2 binding was established according to the first key change (interactions between hesperidin and S RBD/hACE2) vs the second key change (interactions between anti-SARS-CoV-2 drugs and RBD/hACE2) trends. Our findings provide valuable information on the mechanism of RBD/hACE2 binding and on the associated screening strategies for anti-SARS-CoV-2 drugs based on blocking mechanisms of pockets.

| S-EPMC7832953 | biostudies-literature

mouse ACE2 receptor bound to SARS-CoV-2 variant Omicron BA.2.12.1 Spike

Project description: Not available

| EMPIAR-11180 | biostudies-other

mouse ACE2 receptor bound to SARS-CoV-2 variant Omicron BA.1 Spike

Project description: Not available

| EMPIAR-11179 | biostudies-other

Peimine inhibits variants of SARS-CoV-2 cell entry via blocking the interaction between viral spike protein and ACE2.

Project description:Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several vaccines against SARS-CoV-2 have been approved; however, variants of concern (VOCs) can evade vaccine protection. Therefore, developing small compound drugs that directly block the interaction between the viral spike glycoprotein and ACE2 is urgently needed to provide a complementary or alternative treatment for COVID-19 patients. We developed a viral infection assay to screen a library of approximately 126 small molecules and showed that peimine inhibits VOCs viral infections. In addition, a fluorescence resonance energy transfer (FRET) assay showed that peimine suppresses the interaction of spike and ACE2. Molecular docking analysis revealed that peimine exhibits a higher binding affinity for variant spike proteins and is able to form hydrogen bonds with N501Y in the spike protein. These results suggest that peimine, a compound isolated from Fritillaria, may be a potent inhibitor of SARS-CoV-2 variant infection. PRACTICAL APPLICATIONS: In this study, we identified a naturally derived compound of peimine, a major bioactive alkaloid extracted from Fritillaria, that could inhibit SARS-CoV-2 variants of concern (VOCs) viral infection in 293T/ACE2 and Calu-3 lung cells. In addition, peimine blocks viral entry through interruption of spike and ACE2 interaction. Moreover, molecular docking analysis demonstrates that peimine has a higher binding affinity on N501Y in the spike protein. Furthermore, we found that Fritillaria significantly inhibits SARS-CoV-2 viral infection. These results suggested that peimine and Fritillaria could be a potential functional drug and food for COVID-19 patients.

| S-EPMC9353385 | biostudies-literature

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