Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection

Karoyan, Philippe; Vieillard, Vincent; Gómez‐Morales, Luis; Odile, Estelle; Guihot, Amélie; Luyt, Charles‐Édouard; Denis, Alexis; Grondin, Pascal; Lequin, Olivier

doi:10.1038/s42003-021-01736-8

Cited by 97 publications

(108 citation statements)

References 35 publications

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“…In addition to designing RBD blockers that directly disrupt the binding between ACE2 and S protein, another approach is to identify the allosteric binding site and discover allosteric modulators, such as toremifene, to indirectly destabilize the binding between two proteins [ 43 ]. Recently, many advances have been made in the design of vaccine epitopes [ 44 , 45 ], monoclonal antibodies [ 46 , 47 ], and peptides [ 48 ] that target the S protein. Small molecular blockers that also bind to the epitopes of the spike are promising for COIVD-19 treatment.…”

Section: Discussionmentioning

confidence: 99%

Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein

Wang

Yao

et al. 2021

Acta Pharmacol Sin

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An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant K D ) of 0.0947 µM and anti-virus IC 50 of 85.75 µM.

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Section: Discussionmentioning

confidence: 99%

Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein

Wang

Yao

et al. 2021

Acta Pharmacol Sin

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“…To overcome these limitations, further engineering was conducted by fusing ACE2 to the Fc region of the human immunoglobulin IgG1, in order to increase its plasma stability 93 , 94 . Alternatively, the N-terminal helix of ACE2 which contains most of the contacting residues at the binding site was mimicked, and the designed peptides exhibit high anti-SARS-CoV-2 activity in vitro 95 , 96 , 97 . Vice versa , a SARS-CoV-2 RBD-derived hexapeptide YKYRYL has also been proposed to possess inhibitory effect against virus entry by interfering with RBD–ACE2 interaction 98 .…”

Section: Antiviral Therapies Against Sars-cov-2 Cell Entrymentioning

confidence: 99%

SARS-CoV-2 cell entry and targeted antiviral development

Chen

Achi

et al. 2021

Acta Pharmaceutica Sinica B

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19), which threatens human health and public safety. In the urgent campaign to develop anti-SARS-CoV-2 therapies, the initial entry step is one of the most appealing targets. In this review, we summarize the current understanding of SARS-CoV-2 cell entry, and the development of targeted antiviral strategies. Moreover, we speculate upon future directions toward next-generation of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.

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“…One of their most promising peptide-mimics (P10) blocked SARS-CoV-2 human pulmonary cell infection with an IC 50 of 42 nM and 0.03 nM binding affinity ( K d ), as assessed by biolayer interferometry. 36 A recent publication also reported that four stapled peptides show antiviral activity in HT1080/ACE2 cells (IC 50 of 1.9 to 4.1 μM) and A549/ACE2 (IC 50 of 2.2 to 2.8 μM). 37 The most promising of these peptides binds SARS-CoV-2 S-RBD with a K d of 2.2 μM, as determined by SPR.…”

Section: Introductionmentioning

confidence: 94%

Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein

et al. 2021

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The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein–protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, β3, and β4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.

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Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection

Cited by 97 publications

References 35 publications

Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein

Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein

SARS-CoV-2 cell entry and targeted antiviral development

Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein

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