Computational design of antagonist peptides based on the structure of secreted frizzled-related protein-1 (SFRP1) aiming to inhibit Wnt signaling pathway

Mafakher, Ladan; Rismani, Elham; Rahimi, Hamzeh; Enayatkhani, Maryam; Azadmanesh, Kayhan; Teimoori‐Toolabi, Ladan

doi:10.1080/07391102.2020.1835718

Cited by 14 publications

(11 citation statements)

References 86 publications

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“…The molecular dynamic (MD) simulation was carried out to study the stability of the PspA 1-5c+p protein model using GROMACS 2018 [ 56 , 57 ]. The structure was simulated for 85 ns with optimized potential for liquid simulations (OPLS) force field in a 10 A° cubic simulation box of the simple point charge (SPC) as a water molecule type.…”

Section: Methodsmentioning

confidence: 99%

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In-silico design and evaluation of an epitope-based serotype-independent promising vaccine candidate for highly cross-reactive regions of pneumococcal surface protein A

Afshari

Cohan

Sotoodehnejadnematalahi

et al. 2023

J Transl Med

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Background The pathogenicity of pneumococcus with high morbidity, mortality, and multi-drug resistance patterns has been increasing. The limited coverage of the licensed polysaccharide-based vaccines and the replacement of the non-vaccine serotypes are the main reasons for producing a successful serotype-independent vaccine. Pneumococcal surface protein A (PspA) is an extremely important virulence factor and an interesting candidate for conserved protein-based pneumococcal vaccine classified into two prominent families containing five clades. PspA family-elicited immunity is clade-dependent, and the level of the PspA cross-reactivity is restricted to the same family. Methods To cover and overcome the clade-dependent immunity of the PspAs in this study, we designed and tested a PspA1-5c+p vaccine candidate composed of the highest immunodominant coverage of B- and T-cell epitope truncated domain of each clade focusing on two cross-reactive B and C regions of the PspAs. The antigenicity, toxicity, physicochemical properties, 3D structure prediction, stability and flexibility of the designed protein using molecular dynamic (MD) simulation, molecular docking of the construct withHLADRB1*(01:01) and human lactoferrin N-lop, and immune simulation were assessed using immunoinformatics tools. In the experimental section, after intraperitoneal immunization of the mice with Alum adjuvanted recombinant PspA1-5c+p, we evaluated the immune response, cross-reactivity, and functionality of the Anti-PspA1-5c+p antibody using ELISA, Opsonophagocytic killing activity, and serum bactericidal assay. Results For the first time, this work suggested a novel PspA-based vaccine candidate using immunoinformatics tools. The designed PspA1-5c+p protein is predicted to be highly antigenic, non-toxic, soluble, stable with low flexibility in MD simulation, and able to stimulate both humoral and cellular immune responses. The designed protein also could interact strongly with HLADRB1*(01:01) and human lactoferrin N-lop in the docking study. Our immunoinformatics predictions were validated using experimental data. Results showed that the anti-PspA1-5c+p IgG not only had a high titer with strong and same cross-reactivity coverage against all pneumococcal serotypes used but also had high and effective bioactivity for pneumococcal clearance using complement system and phagocytic cells. Conclusion Our findings elucidated the potential application of the PspA1-5c+p vaccine candidate as a serotype-independent pneumococcal vaccine with a strong cross-reactivity feature. Further in-vitro and in-vivo investigations against other PspA clades should be performed to confirm the full protection of the PspA1-5c+p vaccine candidate.

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Section: Methodsmentioning

confidence: 99%

“…The equilibrated system was subjected to MD simulation with two femtoseconds (fs) time steps, which continued until the system was stable. The output trajectory analysis includes Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

In-silico design and evaluation of an epitope-based serotype-independent promising vaccine candidate for highly cross-reactive regions of pneumococcal surface protein A

Afshari

Cohan

Sotoodehnejadnematalahi

et al. 2023

J Transl Med

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“…The regulatory relationship between SFRP1 and the Wnt/β-Catenin signaling pathways, which serve a vital role in atherosclerosis or AMI was illustrated ( Fig. 1D ) ( 41 , 42 ).…”

Section: Resultsmentioning

confidence: 99%

Exosomal microRNA‑4516, microRNA‑203 and SFRP1 are potential biomarkers of acute myocardial infarction

2023

Mol Med Rep

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Acute myocardial infarction (AMI) is a serious disease which threatens public health. Exosomes (exos) contain certain genetic information and are important communication vehicles between cells. In the present study, different exosomal microRNAs (miRs), which exhibit a notable association between expression levels in plasma and AMI were assessed to support the development of new diagnostic and clinical assessment markers of patients with AMI. In total, 93 individuals, including 31 healthy controls and 62 patients with AMI, were recruited for the present study. Data on age, blood pressure, glucose levels, lipid levels and coronary angiography images were collected from the enrolled individuals, and plasma samples were collected. Plasma exos were extracted and verified using ultracentrifugation, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). Exo-miR-4516 and exo-miR-203 in plasma exos were identified by exosomal miRNA sequencing analysis, reverse transcription-quantitative PCR was performed to detect the levels of exo-miR-4516 and exo-miR-203 in plasma exos, and ELISA was performed to detect the levels of secretory frizzled-related protein 1 (SFRP1) in samples. The correlation analysis between exo-miR-4516, exo-miR-203 and SFRP1 in plasma exos and AMI was presented as receiver operating characteristic curves (ROCs) of the SYNTAX score, cardiac troponin I (cTnI), low-density lipoprotein (LDL) and each indicator separately. Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed to predict relevant enrichment pathways. Exos were successfully isolated from plasma by ultracentrifugation, which was confirmed by TEM, NTA and WB. Exo-miR-4516, exo-miR-203 and SFRP1 levels in plasma were significantly higher in the AMI group compared with the healthy control group. ROCs demonstrated that exo-miR-4516, exo-miR-203 and SFRP1 levels had a high diagnostic efficiency in predicting AMI. Exo-miR-4516 was positively correlated with SYNTAX score, and plasma SFRP1 was positively correlated with plasma cTnI and LDL. In conclusion, the data demonstrated that exo-miR-4516, exo-miR-203 and SFRP1 levels could be used in combination to diagnose and assess the severity of AMI. The present study was retrospectively registered (TRN, NCT02123004).

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“…The simulation system was then equilibrated by a constant number of particles, volume, and temperature (NVT) and a constant number of particles, pressure, and temperature (NPT) ensemble. For NVT equilibration through 100 picoseconds, the leap-frog integrator and linear constraint solver (LINCS) algorithm were used [ 49 ]. The PME (particle mesh Ewald) algorithm with a grid spacing of 0.16 nm and a radius cutoff of 1.0 nm was considered for calculating electrostatic interaction.…”

Section: Methodsmentioning

confidence: 99%

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact

Farajzadeh-Dehkordi

Mafakher

Samiee-Rad

et al. 2023

BMC Mol and Cell Biol

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Background Cytochrome P450 4F2 (CYP4F2) enzyme is a member of the CYP4 family responsible for the metabolism of fatty acids, therapeutic drugs, and signaling molecules such as arachidonic acid, tocopherols, and vitamin K. Several reports have demonstrated that the missense variant CYP4F2*3 (V433M) causes decreased activity of CYP4F2 and inter-individual variations in warfarin dose in different ethnic groups. However, the molecular pathogenicity mechanism of missense V433M in CYP4F2 at the atomic level has not yet been completely elucidated. Methods and results In the current study, we evaluated the effect of the V433M substitution on CYP4F2 using 14 different bioinformatics tools. Further molecular dynamics (MD) simulations were performed to assess the impact of the V433M mutation on the CYP4F2 protein structure, stability, and dynamics. In addition, molecular docking was used to illustrate the effect of V433M on its interaction with vitamin K1. Based on our results, the CYP4F2*3 variant was a damaging amino acid substitution with a destabilizing nature. The simulation results showed that missense V433M affects the dynamics and stability of CYP4F2 by reducing its compactness and stability, which means that it tends to change the overall structural conformation and flexibility of CYP4F2. The docking results showed that the CYP4F2*3 variant decreased the binding affinity between vitamin K1 and CYP4F2, which reduced the activity of CYP4F2*3 compared to native CYP4F2. Conclusions This study determined the molecular pathogenicity mechanism of the CYP4F2*3 variant on the human CYP4F2 protein and provided new information for understanding the structure-function relationship of CYP4F2 and other CYP4 enzymes. These findings will aid in the development of effective drugs and treatment options.

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Computational design of antagonist peptides based on the structure of secreted frizzled-related protein-1 (SFRP1) aiming to inhibit Wnt signaling pathway

Cited by 14 publications

References 86 publications

In-silico design and evaluation of an epitope-based serotype-independent promising vaccine candidate for highly cross-reactive regions of pneumococcal surface protein A

In-silico design and evaluation of an epitope-based serotype-independent promising vaccine candidate for highly cross-reactive regions of pneumococcal surface protein A

Exosomal microRNA‑4516, microRNA‑203 and SFRP1 are potential biomarkers of acute myocardial infarction

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact

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