A potential peptide inhibitor of SARS-CoV-2 S and human ACE2 complex

Jaiswal, Grijesh; Yaduvanshi, Shivani; Kumar, Veerendra

doi:10.1080/07391102.2021.1889665

Cited by 6 publications

(3 citation statements)

References 80 publications

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“…The efficacy of recombinant ACE2 in capturing the SARS-CoV-2 S protein has been validated; however, ACE2 is not optimal for intranasal delivery [20][21][22], due to its large size and limited density of binding sites. Instead, peptide inhibitors derived from the S1 protein that have a high affinity for ACE2 are promising candidates [23,24].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ACE2–S Protein Interaction by a Short Functional Peptide with a Boomerang Structure

Wei,

Liu,

Zhang

et al. 2024

Molecules

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Considering the high evolutionary rate and great harmfulness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to develop new pharmacological antagonists. Human angiotensin-converting enzyme-2 (ACE2) functions as a primary receptor for the spike protein (S protein) of SARS-CoV-2. Thus, a novel functional peptide, KYPAY (K5), with a boomerang structure, was developed to inhibit the interaction between ACE2 and the S protein by attaching to the ACE2 ligand-binding domain (LBD). The inhibition property of K5 was evaluated via molecular simulations, cell experiments, and adsorption kinetics analysis. The molecular simulations showed that K5 had a high affinity for ACE2 but a low affinity for the cell membrane. The umbrella sampling (US) simulations revealed a significant enhancement in the binding potential of this functional peptide to ACE2. The fluorescence microscopy and cytotoxicity experiments showed that K5 effectively prevented the interaction between ACE2 and the S protein without causing any noticeable harm to cells. Further flow cytometry research indicated that K5 successfully hindered the interaction between ACE2 and the S protein, resulting in 78% inhibition at a concentration of 100 μM. This work offers an innovative perspective on the development of functional peptides for the prevention and therapy of SARS-CoV-2.

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Section: Introductionmentioning

confidence: 99%

Inhibition of ACE2–S Protein Interaction by a Short Functional Peptide with a Boomerang Structure

Wei,

Liu,

Zhang

et al. 2024

Molecules

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“…Peptides and peptide-derived inhibitors are other attractive alternatives to drug molecules due to their target specificity, effectiveness, safe nature, and ease of synthesis 7 . The inhibitors that mimic natural peptides known as peptidomimetics were reported to bind M pro in SARS-CoV-2, leading the warhead group to catalyze the formation of cysteine-participating covalent bonds 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

A ricin-based peptide BRIP from Hordeum vulgare inhibits Mpro of SARS-CoV-2

Kashyap

Bhardwaj

Chauhan

et al. 2022

Sci Rep

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COVID-19 pandemic caused by SARS-CoV-2 led to the research aiming to find the inhibitors of this virus. Towards this world problem, an attempt was made to identify SARS-CoV-2 main protease (Mpro) inhibitory peptides from ricin domains. The ricin-based peptide from barley (BRIP) was able to inhibit Mpro in vitro with an IC50 of 0.52 nM. Its low and no cytotoxicity upto 50 µM suggested its therapeutic potential against SARS-CoV-2. The most favorable binding site on Mpro was identified by molecular docking and steered molecular dynamics (MD) simulations. The Mpro-BRIP interactions were further investigated by evaluating the trajectories for microsecond timescale MD simulations. The structural parameters of Mpro-BRIP complex were stable, and the presence of oppositely charged surfaces on the binding interface of BRIP and Mpro complex further contributed to the overall stability of the protein-peptide complex. Among the components of thermodynamic binding free energy, Van der Waals and electrostatic contributions were most favorable for complex formation. Our findings provide novel insight into the area of inhibitor development against COVID-19.

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“…In addition to small molecules inhibitors, several groups have proposed decoy inhibitors based on the first two α-helices of ACE2 using different techniques. Some of the publications rely on a linear component of the ACE2 sequence from either the first or second α-helix. − Others also investigated mutations and modifications to the linear sequence of the α-helices. ,− There are only two other publications we are aware of that combine two fragments of ACE2 with a linker but with different sequences. , …”

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confidence: 99%

Engineering an ACE2-Derived Fragment as a Decoy for Novel SARS-CoV-2 Virus

Renzi

Seamann

Ganguly

et al. 2023

ACS Pharmacol. Transl. Sci.

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Entry inhibitors are an important resource in the response against emerging pathogens like the novel SARS-CoV-2, which enters human cells via interaction between the surface spike glycoprotein and the cellular membrane receptor angiotensin-converting enzyme 2 (ACE2). Using a combination of comparative structural analyses of the binding surface of the spike to ACE2, docking experiments, and molecular dynamics simulations, we identified a stable fragment of ACE2 that binds to the spike, is soluble, and is not predicted to bind to its physiological ligand angiotensin II. From this fragment we computationally designed and experimentally validated a smaller, stable peptide that disrupts ACE2-spike interaction at nanomolar concentrations, suggesting its potential use as a decoy that could interfere with viral binding by competition.

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A potential peptide inhibitor of SARS-CoV-2 S and human ACE2 complex

Cited by 6 publications

References 80 publications

Inhibition of ACE2–S Protein Interaction by a Short Functional Peptide with a Boomerang Structure

Inhibition of ACE2–S Protein Interaction by a Short Functional Peptide with a Boomerang Structure

A ricin-based peptide BRIP from Hordeum vulgare inhibits Mpro of SARS-CoV-2

Engineering an ACE2-Derived Fragment as a Decoy for Novel SARS-CoV-2 Virus

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