Chimeric Glutathione S-Transferases Containing Inserts of Kininogen Peptides

Bentley, Amber A.; Merkulov, Sergei; Peng, Yi; Rozmarynowycz, Rita; Qi, Xiaoping; Pusztai-Carey, Marianne; Merrick, William C.; Yee, Vivien C.; McCrae, Keith R.; Komar, Anton A.

doi:10.1074/jbc.m112.372854

Cited by 3 publications

(2 citation statements)

References 43 publications

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“…Secondly, DTT has a rigid tertiary structure composed entirely of α-helices and loops ( Fig 1B ). Therefore, it potentially tolerates transplantation of a foreign peptide and renders the peptide a more stable conformation [ 24 , 25 ]. Moreover, DTT can be expressed in E .…”

Section: Resultsmentioning

confidence: 99%

A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice

Zhang

Wang

et al. 2016

PLoS ONE

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The TNF-α biological inhibitors have significantly improved the clinical outcomes of many autoimmune diseases, in particular rheumatoid arthritis. However, the practical uses are limited due to high costs and the risk of anti-drug antibody responses. Attempts to develop anti-TNF-α vaccines have generated encouraging data in animal models, however, data from clinical trials have not met expectations. In present study, we designed a TNF-α epitope-scaffold immunogen DTNF7 using the transmembrane domain of diphtheria toxin, named DTT as a scaffold. Molecular dynamics simulation shows that the grafted TNF-α epitope is entirely surface-exposed and presented in a native-like conformation while the rigid helical structure of DTT is minimally perturbed, thereby rendering the immunogen highly stable. Immunization of mice with alum formulated DTNF7 induced humoral responses against native TNF-α, and the antibody titer was sustained for more than 6 months, which supports a role of the universal CD4 T cell epitopes of DTT in breaking self-immune tolerance. In a mouse model of rheumatoid arthritis, DTNF7-alum vaccination markedly delayed the onset of collagen-induced arthritis, and reduced incidence as well as clinical score. DTT is presumed safe as an epitope carrier because a catalytic inactive mutant of diphtheria toxin, CRM197 has good clinical safety records as an active vaccine component. Taken all together, we show that DTT-based epitope vaccine is a promising strategy for prevention and treatment of autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice

Zhang

Wang

et al. 2016

PLoS ONE

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“…PPK and HMWK concentrations were lower in hepatosplenic schistosomiasis patients, when compared with the control group [ 173 , 174 ]. A therapeutic approach employing a short human kininogen insertion into S. japonicum glutathione S-transferases, ameliorated their biological activity, and inhibited human umbilical vein endothelial cell proliferation [ 175 ].…”

Section: Kinins and Their Implication In Protozoan And Parasite Inmentioning

confidence: 99%

Kinins and Their Receptors in Infectious Diseases

2020

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Kinins and their receptors have been implicated in a series of pathological alterations, representing attractive pharmacological targets for several diseases. The present review article aims to discuss the role of the kinin system in infectious diseases. Literature data provides compelling evidence about the participation of kinins in infections caused by diverse agents, including viral, bacterial, fungal, protozoan, and helminth-related ills. It is tempting to propose that modulation of kinin actions and production might be an adjuvant strategy for management of infection-related complications.

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Molecular Peptide Grafting as a Tool to Create Novel Protein Therapeutics

Komar

2023

Molecules

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The study of peptides (synthetic or corresponding to discrete regions of proteins) has facilitated the understanding of protein structure–activity relationships. Short peptides can also be used as powerful therapeutic agents. However, the functional activity of many short peptides is usually substantially lower than that of their parental proteins. This is (as a rule) due to their diminished structural organization, stability, and solubility often leading to an enhanced propensity for aggregation. Several approaches have emerged to overcome these limitations, which are aimed at imposing structural constraints into the backbone and/or sidechains of the therapeutic peptides (such as molecular stapling, peptide backbone circularization and molecular grafting), therefore enforcing their biologically active conformation and thus improving their solubility, stability, and functional activity. This review provides a short summary of approaches aimed at enhancing the biological activity of short functional peptides with a particular focus on the peptide grafting approach, whereby a functional peptide is inserted into a scaffold molecule. Intra-backbone insertions of short therapeutic peptides into scaffold proteins have been shown to enhance their activity and render them a more stable and biologically active conformation.

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Chimeric Glutathione S-Transferases Containing Inserts of Kininogen Peptides

Cited by 3 publications

References 43 publications

A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice

A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice

Kinins and Their Receptors in Infectious Diseases

Molecular Peptide Grafting as a Tool to Create Novel Protein Therapeutics

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