Computational Design of Antiangiogenic Peptibody by Fusing Human IgG1 Fc Fragment and HRH Peptide: Structural Modeling, Energetic Analysis, and Dynamics Simulation of Its Binding Potency to VEGF Receptor

AbstractAntiangiogenic therapies targeting vascular endothelial growth factor (VEGF)-A have been commonly used in clinics to treat cancers over the past decade. However, their clinical efficacy has been limited, with drawbacks including the acquisition of resistance and activation of compensatory pathways resulting from elevated circulating VEGF-B and placental growth factor (PlGF) levels. Thus, we developed a novel VEGF-Trap, KP-VR2, which can neutralize VEGF-A, VEGF-B, and PlGF to mediate these problems. KP-VR2 consists of two consecutive second Ig-like domains (D2s) of VEGF receptor 1 (VEGFR-1) fused to human IgG1 Fc. KP-VR2 showed more potent decoy activity than the current VEGF-Trap against VEGF and PlGF. Most importantly, two consecutive D2s of VEGFR-1 can generate two putative binding sites, resulting in a significant improvement in binding capacity. These advances resulted in stronger antitumor efficacy in implanted tumor models than aflibercept and bevacizumab. Overall, the results of this study highlight KP-VR2 as a promising therapeutic candidate for further clinical drug development.

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An In Silico Immunogenicity Analysis for PbHRH: An Antiangiogenic Peptibody by Fusing HRH Peptide and Human IgG1 Fc Fragment

Current Bioinformatics ◽

10.2174/1574893614666190730104348 ◽

2020 ◽

Vol 15 (6) ◽

pp. 547-553

Author(s):

Lin Ning ◽

Jiang Huang ◽

Bifang He ◽

Juanjuan Kang

Keyword(s):

Population Distribution ◽

Binding Prediction ◽

Mhc I ◽

Fc Fragment ◽

Mhc Ii ◽

Bioinformatics Tools ◽

Future Improvement ◽

Human Igg1 ◽

Simulation Results ◽

Novel Strategy

Background: Peptibodies, the hybrid of peptides and antibodies, represent a novel strategy in therapeutic use. Previously, we computationally designed an antiangiogenic peptibody PbHRH, which fused the HRH peptide with angiogenesis-suppressing effect and human IgG1 Fc fragment using Romiplostim as template. Molecular modeling and simulation results indicated that it would be a potential drug for the treatment of those angiogenesis related pathological disorders. However, its immunogenicity is not known. Methods: Several bioinformatics tools are used to predict the potential epitopes for the evaluation of the immunogenicity of PbHRH. Romiplostim is set as the control. IEDB-recommended method is used in MHC-I and MHC-II binding prediction, and the IEDB web server (http://tools.iedb.org/immunogenicity/) is used to determine the MHC-I immunogenicity of each peptide. Results: In this work, some peptides are predicted to have the potential ability to bind to MHC-I and MHC-II molecules both in PbHRH and Romiplostim as the potential epitopes. Most of these selected peptides are exactly the same. Allele frequency analysis shows a low population distribution. Combined with the analysis of MHC-I immunogenicity prediction, both HRH and PbHRH show low immunogenicity. Conclusion: Some potential epitopes which could bind to both MHC-I and MHC-II molecules are predicted using bioinformatics tools. The comparative analysis with Romiplostim and the results of MHC-I immunogenicity prediction indicate the low immunogenicity of both HRH and PbHRH. Thus, we form a strategy to evaluate the immunogenicity of peptibodies for the future improvement.

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Perturbation of Thermal Unfolding and Aggregation of Human IgG1 Fc Fragment by Hofmeister Anions

Molecular Pharmaceutics ◽

10.1021/mp300378y ◽

2013 ◽

Vol 10 (2) ◽

pp. 619-630 ◽

Cited By ~ 16

Author(s):

Jian Zhang-van Enk ◽

Bruce D. Mason ◽

Lei Yu ◽

Le Zhang ◽

Wael Hamouda ◽

...

Keyword(s):

Thermal Unfolding ◽

Fc Fragment ◽

Human Igg1 ◽

Hofmeister Anions

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Equilibrium and pre-equilibrium fluorescence spectroscopic studies of the binding of a single-immunoglobulin-binding domain derived from protein G to the Fc fragment from human IgG1

Biochemical Journal ◽

10.1042/bj3100177 ◽

1995 ◽

Vol 310 (1) ◽

pp. 177-184 ◽

Cited By ~ 12

Author(s):

K N Walker ◽

S P Bottomley ◽

A G Popplewell ◽

B J Sutton ◽

M G Gore

Keyword(s):

Protein A ◽

Spectroscopic Studies ◽

Binding Domain ◽

Protein G ◽

Binding Interaction ◽

Fc Fragment ◽

Igg Binding ◽

Immunoglobulin Binding Protein ◽

Human Igg1 ◽

Immunoglobulin Binding

A single-immunoglobulin-binding protein based upon the C2 domain of Protein G from Streptococcus has been shown to bind tightly to the Fc fragment of IgG1. The binding interaction results in a decrease in the fluorescence intensity from the sole Trp residue (Trp-48) in this domain. This spectral change has been used to monitor the binding interactions between the two proteins using equilibrium and pre-equilibrium fluorescence spectroscopy. Comparison of the data from the two techniques suggests that a conformational change occurs after the initial formation of the complex. Mutagenesis studies have shown that the Trp residue is important for binding and that replacement by a Phe residue is important for binding and that replacement by a Phe residue leads to a 300-fold decrease in the affinity for Fc gamma 1. Determination of the rate constants kon and koff at different values of pH between 4.0 and 9.0 suggest that variations in Kd are mediated predominantly by changes in kon. Competition experiments between SpG1 and a single-IgG-binding domain from Protein A from Staphylococcus aureus have been used to determine the affinity of the latter for Fc gamma 1.

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Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

Molecules ◽

10.3390/molecules26092742 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2742

Author(s):

Sadaf Shehzad ◽

Rajan Pandey ◽

Pawan Malhotra ◽

Dinesh Gupta

Keyword(s):

Binding Affinity ◽

High Throughput ◽

In Silico ◽

Protein Quality ◽

Simulation Analysis ◽

Computational Design ◽

Cellular Protein ◽

Dynamics Simulation ◽

Stable Complex ◽

In Silico Screening

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.

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Stabilisation of the Fc Fragment of Human IgG1 by Engineered Intradomain Disulfide Bonds

PLoS ONE ◽

10.1371/journal.pone.0030083 ◽

2012 ◽

Vol 7 (1) ◽

pp. e30083 ◽

Cited By ~ 41

Author(s):

Gordana Wozniak-Knopp ◽

Johannes Stadlmann ◽

Florian Rüker

Keyword(s):

Disulfide Bonds ◽

Fc Fragment ◽

Human Igg1

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Molecular Docking and Dynamics Simulation Revealed Ivermectin as Potential Drug against Schistosoma-Associated Bladder Cancer Targeting Protein Signaling: Computational Drug Repositioning Approach

Medicina ◽

10.3390/medicina57101058 ◽

2021 ◽

Vol 57 (10) ◽

pp. 1058

Author(s):

Arif Jamal Siddiqui ◽

Mohammad Faheem Khan ◽

Walid Sabri Hamadou ◽

Manish Goyal ◽

Sadaf Jahan ◽

...

Keyword(s):

Bladder Cancer ◽

Molecular Docking ◽

Simulation Analysis ◽

Drug Repositioning ◽

Drug Repurposing ◽

Dynamics Simulation ◽

Vegf Receptor ◽

Protein Signaling ◽

Urogenital Schistosomiasis ◽

Potent Drug

Urogenital schistosomiasis is caused by Schistosoma haematobium (S. haematobium) infection, which has been linked to the development of bladder cancer. In this study, three repurposing drugs, ivermectin, arteether and praziquantel, were screened to find the potent drug-repurposing candidate against the Schistosoma-associated bladder cancer (SABC) in humans by using computational methods. The biology of most glutathione S-transferases (GSTs) proteins and vascular endothelial growth factor (VEGF) is complex and multifaceted, according to recent evidence, and these proteins actively participate in many tumorigenic processes such as cell proliferation, cell survival and drug resistance. The VEGF and GSTs are now widely acknowledged as an important target for antitumor therapy. Thus, in this present study, ivermectin displayed promising inhibition of bladder cancer cells via targeting VEGF and GSTs signaling. Moreover, molecular docking and molecular dynamics (MD) simulation analysis revealed that ivermectin efficiently targeted the binding pockets of VEGF receptor proteins and possessed stable dynamics behavior at binding sites. Therefore, we proposed here that these compounds must be tested experimentally against VEGF and GST signaling in order to control SABC. Our study lies within the idea of discovering repurposing drugs as inhibitors against the different types of human cancers by targeting essential pathways in order to accelerate the drug development cycle.

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