HD5 and LL-37 Inhibit SARS-CoV and SARS-CoV-2 Binding to Human ACE2 by Molecular Simulation

Li, Daixi; Chen, Peiqin; Shi, Ting; Mehmood, Aamir; Qiu, Jingfei

doi:10.1007/s12539-021-00462-3

Cited by 22 publications

(12 citation statements)

References 45 publications

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“…The effect of AMPs on virus infections appears to be specific for the virus, AMP, as well as the target cell. First evidence for LL-37 has been reported, showing its binding to the SARS-CoV-2 spike protein and its inhibitory action on the binding of the spike protein to its entry receptor using binding competition studies [ 37 , 42 ]. In another study, a high structural similarity between LL-37 and the N-terminal helix of the receptor-binding domain of SARS-CoV-2 was reported [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

In vitro Screening of Herbal Medicinal Products for Their Supportive Curing Potential in the Context of SARS-CoV-2

Tran

Peterburs

Seibel

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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COVID-19 herbal medicinal products may have the potential for symptom relief in nonsevere or moderate disease cases. In this in vitro study we screened the five herbal medicinal products Sinupret extract (SINx), Bronchipret thyme-ivy (BRO-TE), Bronchipret thyme-primula (BRO TP), Imupret (IMU), and Tonsipret (TOP) with regard to their potential to (i) interfere with the binding of the human angiotensin-converting enzyme 2 (ACE2) receptor with the SARS-CoV-2 spike S1 protein, (ii) modulate the release of the human defensin HBD1 and cathelicidin LL-37 from human A549 lung cells upon spike S1 protein stimulation, and (iii) modulate the release of IFN-γ from activated human peripheral blood mononuclear cells (PBMC). The effect of the extracts on the interaction of spike S1 protein and the human ACE2 receptor was measured by ELISA. The effects on the intracellular IFN-γ expression in stimulated human PBMC were measured by flow cytometry. Regulation of HBD1 and LL-37 expression and secretion was assessed in 25 d long-term cultured human lung A549 epithelial cells by RT-PCR and ELISA. IMU and BRO-TE concentration-dependently inhibited the interaction between spike S1 protein and the ACE2 receptor. SINx, TOP, and BRO-TE significantly upregulated the intracellular expression of anti-viral IFN-γ from stimulated PBMC. Cotreatment of A549 cells with IMU or BRO TP together with SARS-CoV-2 spike protein significantly upregulated mRNA expression (IMU) and release of HBD1 (IMU and BRO TP) and LL-37 (BRO TP). The in vitro screening results provide first evidence for an immune-activating potential of some of the tested herbal medicinal extracts in the context of SARS-CoV-2. Whether these could be supportive in symptom relief or curing from SARS-CoV-2 infection needs deeper understanding of the observations.

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Section: Discussionmentioning

confidence: 99%

In vitro Screening of Herbal Medicinal Products for Their Supportive Curing Potential in the Context of SARS-CoV-2

Tran

Peterburs

Seibel

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…The binding free energy of the system was estimated through the following equation,

The formula, ΔG bind is the binding free energy, ΔE MM is the intramolecular energy in vacuum, including electrostatic interaction (ΔE elec ), van der Waals force (ΔE vdw ), and Δ ΔG sol is solvation free energy, including polar solvation energy (ΔG PB ) (calculated by PB equation) and non-polar solvation energy (ΔG SASA ) (obtained by calculating molecular accessible surface area). The entropic energy (TΔS) is usually ignored because of its estimation is a slow process and yields a small value [ 53 ]. In this study, the binding free energy of the complex does not include the energy contributed by entropy.…”

Section: Methodsmentioning

confidence: 99%

Bionics design of affinity peptide inhibitors for SARS-CoV-2 RBD to block SARS-CoV-2 RBD-ACE2 interactions

Liu

Jiang

et al. 2023

Heliyon

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“…35 Human alpha defensin type 5 (HD5) was found to inhibit the invasion of CoV-2, 36 as did LL-37. 37 Human β defensins (hBDs) are AMPs secreted by the human innate immune system. They provide a first line of defense against fungi, yeast, both Gram-positive and Gram-negative bacteria, and various infectious pathogens, including enveloped viruses.…”

Section: Introductionmentioning

confidence: 99%

“…Human-derived AMPs, such as defensins and cathelicidin LL-37, play a crucial role in early pulmonary defense against viruses . Human alpha defensin type 5 (HD5) was found to inhibit the invasion of CoV-2, as did LL-37 . Human β defensins (hBDs) are AMPs secreted by the human innate immune system.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations on Spike Protein Mutants Binding with Human β Defensin Type 2

Zhang,

2024

J. Phys. Chem. B

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Human β defensin type 2 (hBD-2), a cationic cysteine-rich peptide secreted from the human innate immune system, can bind Spike-RBD at the same site as receptor ACE2, thus blocking viral entry into ACE2-expressing cells. In order to find out the impact of CoV-2 mutations on hBD-2's antiviral activity, it is important to investigate the binding and interaction of hBD-2 with RBD mutants. All-atom molecular dynamics simulations were conducted on typical RBD mutants, including N501Y, E484K, P479S, T478I, S477N, N439K, K417N, and N501Y-E484K-K417N, binding with hBD-2. Starting from the stable binding structure of hBD-2 and wt-RBD and ClusPro and HADDOCK docking-predicted initial structures, the RBD variants bound with hBD-2 simulations were set up, and NAMD simulations were conducted. Based on the structure and dynamics analysis, it was found that most RBD variants can still form a similar number of hydrogen bonds with hBD-2, in addition to having a similar-sized buried surface area (BSA) and a similar binding interface to the RBD wildtype. However, the RBD triple mutant formed a less stable binding structure with hBD-2 than other variants. Additionally, the free energy perturbation (FEP) method was applied to calculate the contribution of key mutant residues to the binding and the free energy change caused by the mutations. The result shows that N439K, K417N, and the trimutation increase the binding free energy of RBD with hBD-2; thus, RBD should bind less stably with hBD-2. E484K decreases the binding free energy, thus it should bind more stably with hBD-2, while N501Y, S477N, T478I, and P479S almost do not change the binding free energy with hBD-2. The MM-GBSA method predicted the binding interaction energy which shows that the trimutant should be able to escape the binding with hBD-2 but N501Y should not. The result can provide insight into understanding the functional mechanism of hBD-2 combating SARS-CoV-2 mutants.

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HD5 and LL-37 Inhibit SARS-CoV and SARS-CoV-2 Binding to Human ACE2 by Molecular Simulation

Cited by 22 publications

References 45 publications

In vitro Screening of Herbal Medicinal Products for Their Supportive Curing Potential in the Context of SARS-CoV-2

In vitro Screening of Herbal Medicinal Products for Their Supportive Curing Potential in the Context of SARS-CoV-2

Bionics design of affinity peptide inhibitors for SARS-CoV-2 RBD to block SARS-CoV-2 RBD-ACE2 interactions

Molecular Dynamics Simulations on Spike Protein Mutants Binding with Human β Defensin Type 2

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