Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region

Pourmand, Saeed; Zareei, Sara; Shahlaei, Mohsen; Moradi, Sajad

doi:10.1016/j.compbiomed.2022.105625

Cited by 12 publications

(8 citation statements)

References 66 publications

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“…Particularly, when CDK9 was complexed with mp29, the greatest amino acid fluctuation was observed. These findings align with the results obtained from other molecular dynamics analyses ( Pourmand et al, 2022 ), suggesting that mp29 induces higher mobility in the protein, potentially leading to partial structural instability. The analysis of Rg, which serves as an indicator of protein compactness and stability ( Kianipour et al, 2022 ), revealed that the maximum and minimum average Rg values were in the complexes of mp3 (2.264 ± 0.019 nm) and mp29 (2.192 ± 0.025 nm) with CDK9, respectively.…”

Section: Resultssupporting

confidence: 91%

Section: Residuessupporting

confidence: 91%

“…However, previous studies have employed phage biopanning technique and alanine scanning analysis to design mutant peptide inhibitors against cancer targets (Saw and Song, 2019;Shahab et al, 2023). Moreover, a similar methodology has been employed to design effective mutant peptides that inhibit the interaction between the spike protein of SARS-CoV-2 and the human ACE2 receptor (Pourmand et al, 2022). Note: The residues of temp2 were highlighted in Bold.…”

Section: Residuesmentioning

confidence: 99%

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Structure-guided design and cloning of peptide inhibitors targeting CDK9/cyclin T1 protein-protein interaction

Taghizadeh,

Taherishirazi,

Niazi

et al. 2024

Front. Pharmacol.

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CDK9 (cyclin-dependent kinase 9) plays a significant role in numerous pathological conditions, such as HIV-1 infection and cancer. The interaction between CDK9 and cyclin T1 is crucial for maintaining the kinase’s active state. Therefore, targeting this protein-protein interaction offers a promising strategy for inhibiting CDK9. In this study, we aimed to design and characterize a library of mutant peptides based on the binding region of cyclin T1 to CDK9. Using Osprey software, a total of 7,776 mutant peptides were generated. After conducting a comprehensive analysis, three peptides, namely, mp3 (RAADVEGQRKRRE), mp20 (RAATVEGQRKRRE), and mp29 (RAADVEGQDKRRE), were identified as promising inhibitors that possess the ability to bind to CDK9 with high affinity and exhibit low free binding energy. These peptides exhibited favorable safety profiles and displayed promising dynamic behaviors. Notably, our findings revealed that the mp3 and mp29 peptides interacted with a conserved sequence in CDK9 (residues 60–66). In addition, by designing the structure of potential peptides in the plasmid vector pET28a (+), we have been able to pave the way for facilitating the process of their recombinant production in an Escherichia coli expression system in future studies. Predictions indicated good solubility upon overexpression, further supporting their potential for downstream applications. While these results demonstrate the promise of the designed peptides as blockers of CDK9 with high affinity, additional experimental studies are required to validate their biological activity and assess their selectivity. Such investigations will provide valuable insights into their therapeutic potential and pave the way for the future development of peptide-based inhibitors targeting the CDK9-cyclin T1 complex.

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Section: Resultssupporting

confidence: 91%

Section: Residuessupporting

confidence: 91%

Section: Residuesmentioning

confidence: 99%

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Structure-guided design and cloning of peptide inhibitors targeting CDK9/cyclin T1 protein-protein interaction

Taghizadeh,

Taherishirazi,

Niazi

et al. 2024

Front. Pharmacol.

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“…To evaluate changes in the protein 3-D structure and its stability, SASA value was computed, which represents the solvent accessibility of the protein. This analysis predicts the number of protein surface amino acids that can be accessible to the solvent [ 54 , 55 ]. A higher SASA value indicates protein unfolding reactions.…”

Section: Resultsmentioning

confidence: 99%

In silico study of alkaloids with quercetin nucleus for inhibition of SARS-CoV-2 protease and receptor cell protease

Mohebbi,

Eskandarzadeh,

Zangi

et al. 2024

PLoS ONE

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Covid-19 disease caused by the deadly SARS-CoV-2 virus is a serious and threatening global health issue declared by the WHO as an epidemic. Researchers are studying the design and discovery of drugs to inhibit the SARS-CoV-2 virus due to its high mortality rate. The main Covid-19 virus protease (Mpro) and human transmembrane protease, serine 2 (TMPRSS2) are attractive targets for the study of antiviral drugs against SARS-2 coronavirus. Increasing consumption of herbal medicines in the community and a serious approach to these drugs have increased the demand for effective herbal substances. Alkaloids are one of the most important active ingredients in medicinal plants that have wide applications in the pharmaceutical industry. In this study, seven alkaloid ligands with Quercetin nucleus for the inhibition of Mpro and TMPRSS2 were studied using computational drug design including molecular docking and molecular dynamics simulation (MD). Auto Dock software was used to evaluate molecular binding energy. Three ligands with the most negative docking score were selected to be entered into the MD simulation procedure. To evaluate the protein conformational changes induced by tested ligands and calculate the binding energy between the ligands and target proteins, GROMACS software based on AMBER03 force field was used. The MD results showed that Phyllospadine and Dracocephin-A form stable complexes with Mpro and TMPRSS2. Prolinalin-A indicated an acceptable inhibitory effect on Mpro, whereas it resulted in some structural instability of TMPRSS2. The total binding energies between three ligands, Prolinalin-A, Phyllospadine and Dracocephin-A and two proteins MPro and TMRPSS2 are (-111.235 ± 15.877, - 75.422 ± 11.140), (-107.033 ± 9.072, -84.939 ± 10.155) and (-102.941 ± 9.477, - 92.451 ± 10.539), respectively. Since the binding energies are at a minimum, this indicates confirmation of the proper binding of the ligands to the proteins. Regardless of some Prolinalin-A-induced TMPRSS2 conformational changes, it may properly bind to TMPRSS2 binding site due to its acceptable binding energy. Therefore, these three ligands can be promising candidates for the development of drugs to treat infections caused by the SARS-CoV-2 virus.

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“…Computational techniques and molecular dynamics simulations have been widely applied in COVID-19-related studies in different areas such as interactions between the virus and human its human receptors (Spinello et al, 2020;Wang et al, 2020), mutations of SARS-CoV-2 (Shah et al, 2020;Kullappan et al, 2021;Luan et al, 2021;Spinello et al, 2021), characteristics of SARS-CoV-2 proteins (Kordzadeh and Saadatabadi, 2021;Zhang et al, 2022;Bignon et al, 2022;Borisõek et al, 2021), and drug discovery (Aallaei et al, 2021;Bayati and Ebrahimi, 2021;Mora et al, 2022). In our previous study, we designed peptide inhibitors with the last strategy inspired by the RBD domain of the SARS-CoV-2 spike (Pourmand et al, 2022). Here, computational mutagenesis was applied to designing new peptide inhibitors to provide physical disturbance against SARS-CoV-2 and ACE2 interaction inspired by the RBD-binding region of ACE2.…”

Section: Introductionmentioning

confidence: 99%

Design of novel disturbing peptides against ACE2 SARS-CoV-2 spike-binding region by computational approaches

2022

Self Cite

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The SARS-CoV-2, the virus which is responsible for COVID-19 disease, employs its spike protein to recognize its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequently enters the host cell. In this process, the receptor-binding domain (RBD) of the spike has an interface with the α1-helix of the peptidase domain (PD) of ACE2. This study focuses on the disruption of the protein-protein interaction (PPI) of RBD-ACE2. Among the residues in the template (which was extracted from the ACE2), those with unfavorable energies were selected for substitution by mutagenesis. As a result, a library of 140 peptide candidates was constructed and the binding affinity of each candidate was evaluated by molecular docking and molecular dynamics simulations against the α1-helix of ACE2. Finally, the most potent peptides P23 (GFNNYFPHQSYGFMPTNGVGY), P28 (GFNQYFPHQSYGFPPTNGVGY), and P31 (GFNRYFPHQSYGFCPTNGVGY) were selected and their dynamic behaviors were studied. The results showed peptide inhibitors increased the radius, surface accessible area, and overall mobility of residues of the protein. However, no significant alteration was seen in the key residues in the active site. Meanwhile, they can be proposed as promising agents against COVID-19 by suppressing the viral attachment and curbing the infection at its early stage. The designed peptides showed potency against beta, gamma, delta, and omicron variants of SARS-CoV-2.

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Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region

Cited by 12 publications

References 66 publications

Structure-guided design and cloning of peptide inhibitors targeting CDK9/cyclin T1 protein-protein interaction

Structure-guided design and cloning of peptide inhibitors targeting CDK9/cyclin T1 protein-protein interaction

In silico study of alkaloids with quercetin nucleus for inhibition of SARS-CoV-2 protease and receptor cell protease

Design of novel disturbing peptides against ACE2 SARS-CoV-2 spike-binding region by computational approaches

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