ABD-Derived Protein Blockers of Human IL-17 Receptor A as Non-IgG Alternatives for Modulation of IL-17-Dependent Pro-Inflammatory Axis

Hlavničková, Marie; Kuchař, Milan; Osička, Radim; Vaňková, Lucie; Petroková, Hana; Malý, Michal; Černý, Jiří; Arenberger, Petr; Malý, Petr

doi:10.3390/ijms19103089

Cited by 10 publications

(8 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this work, we generated insoluble fibrin-targeted protein binders useful for development of thrombus imaging agents. For this non-immunoglobulin approach, combinatorial library derived from 5.5 kDa albumin-binding domain of streptococcal protein G was chosen as this library of theoretical complexity up to 10 14 protein variants has already provided binders of several important protein targets [31,34,41], some of them with nanomolar or even sub-nanomolar binding affinity [30,32,33]. To stabilize small protein binders, 305 amino acid helical TolA protein is being used to form 38 kDa fusion binding variants.…”

Section: Discussionmentioning

confidence: 99%

“…This approach represents a valuable alternative for production of robust and high-affinity binders with a required selectivity. In this study, we used a highly complex combinatorial library derived from scaffold of albumin-binding domain (ABD) of streptococcal protein G [30][31][32], and ribosome display, to identify fibrin-specific protein binders that could be used as components for targeted delivery of nanoliposomes to human thrombi in vitro and in vivo. We demonstrate that one of the selected candidates preferentially binds to insoluble fibrin as well as to human thrombus in vitro.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Human Thrombus by Liposomes Modified with Anti-Fibrin Protein Binders

et al. 2019

Self Cite

View full text Add to dashboard Cite

Development of tools for direct thrombus imaging represents a key step for diagnosis and treatment of stroke. Nanoliposomal carriers of contrast agents and thrombolytics can be functionalized to target blood thrombi by small protein binders with selectivity for fibrin domains uniquely formed on insoluble fibrin. We employed a highly complex combinatorial library derived from scaffold of 46 amino acid albumin-binding domain (ABD) of streptococcal protein G, and ribosome display, to identify variants recognizing fibrin cloth in human thrombus. We constructed a recombinant target as a stretch of three identical fibrin fragments of 16 amino acid peptide of the Bβ chain fused to TolA protein. Ribosome display selection followed by large-scale Enzyme-Linked ImmunoSorbent Assay (ELISA) screening provided four protein variants preferentially binding to insoluble form of human fibrin. The most specific binder variant D7 was further modified by C-terminal FLAG/His-Tag or double His-tag for the attachment onto the surface of nanoliposomes via metallochelating bond. D7-His-nanoliposomes were tested using in vitro flow model of coronary artery and their binding to fibrin fibers was demonstrated by confocal and electron microscopy. Thus, we present here the concept of fibrin-targeted binders as a platform for functionalization of nanoliposomes in the development of advanced imaging tools and future theranostics.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Human Thrombus by Liposomes Modified with Anti-Fibrin Protein Binders

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both REX and ILP binders were able to compete with p19 binding to IL-23R in vitro, and inhibited IL-23-mediated expansion of primary human Th17 cells [65,66]. This ABD-based strategy has been also used to generate IL-17a binders (ARS binders) that prevented hIL-17A binding to its cell-surface receptor [67]. Taking this research one step closer to application in humans, recombinant strains of Lactococcus lactis expressing REX009 and REX115 ligands (hIL-23R binders) [68] and LP317 ligand (hIL-23 binder) [69] have been created.…”

Section: Il-23/il-23r Structure and Bindingmentioning

confidence: 99%

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Pastor-Fernández

Mariblanca

Navarro

2020

Cells

View full text Add to dashboard Cite

The interleukin 23 (IL-23) is a key pro-inflammatory cytokine in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators, such as IL-17, IL-22, granulocyte-macrophage colony-stimulating (GM-CSF), or the tumor necrosis factor (TNFα) by target populations, mainly Th17 and IL-17-secreting TCRγδ cells (Tγδ17). Due to their pivotal role in inflammatory diseases, IL-23 and its downstream effector molecules have emerged as attractive therapeutic targets, leading to the development of neutralizing antibodies against IL-23 and IL-17 that have shown efficacy in different inflammatory diseases. Despite the success of monoclonal antibodies, there are patients that show no response or partial response to these treatments. Thus, effective therapies for inflammatory diseases may require the combination of multiple immune-modulatory drugs to prevent disease progression and to improve quality of life. Alternative strategies aimed at inhibiting intracellular signaling cascades using small molecule inhibitors or interfering peptides have not been fully exploited in the context of IL-23-mediated diseases. In this review, we discuss the current knowledge about proximal signaling events triggered by IL-23 upon binding to its membrane receptor to bring to the spotlight new opportunities for therapeutic intervention in IL-23-mediated pathologies.

show abstract

“…According to the KEGG pathway analysis, coexpressed genes in the green module mainly participate in the TNF, IL‐17, NOD‐like receptor, and MAPK signalling pathways. These pathways are mainly involved in inflammation and the progression of OA . The MAPK signalling pathway, one of intracellular serine‐threonine protein kinase superfamily members, is the centre of multiple signal transduction pathways .…”

Section: Discussionmentioning

confidence: 99%

Identification and functional analysis of long non‐coding RNAs in the synovial membrane of osteoarthritis patients

Shui

Xie

Chen

et al. 2020

Cell Biochemistry & Function

View full text Add to dashboard Cite

Osteoarthritis (OA), the most common chronic joint disease in the elderly, has become a significant economic burden for families and societies worldwide. Although treatments are continually improving, current drugs only target joint pain, with no effective therapies modifying OA progression. Long noncoding RNAs (lncRNAs), which have received increasing attention in recent years, are abnormally expressed in OA cartilage. In the present study, weighted coexpression network analysis (WGCNA) was applied to identify modules related to certain OA clinical traits. In total, 4404 coding genes and 161 lncRNAs were differentially expressed based on two OA expression profile data sets and normal control samples. Subsequently, 11 independent modules were acquired, and the green module, with a total of 49 hub genes, was identified as the most relevant to OA. These hub genes were validated using the GSE12021 data set. There was only one lncRNA among the hub genes, namely, NONHSAG034351. Thus, we further explored the function of NONHSAG034351‐related genes in the network. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that NONHSAG034351‐associated genes are involved in the response to lipopolysaccharide, angiogenesis, tumour necrosis factor (TNF) signalling, and mitogen‐activated protein kinase (MAPK) signalling pathways. In conclusion, we identified modules through WGCNA related to OA clinical traits. NONHSAG034351, the only hub‐lncRNA, was downregulated in OA synovial tissue and might play a significant role in the pathological progression of this disease. Our findings have important clinical implications and could provide novel biomarkers that indicate the molecular mechanisms of OA and act as potential therapeutic targets. Significance of this study Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in osteoarthritis (OA), which is the most common chronic joint disease among the elderly. In the present study, we report the expression profiles of lncRNAs in OA and the identification of modules through WGCNA related to OA clinical traits. NONHSAG034351, the only hub‐lncRNA identified to be downregulated in the synovial tissue of OA patients, might play a significant role in the pathological progression of OA. Furthermore, our findings provide novel biomarkers associated with the molecular mechanisms underlying OA pathogenesis, thus implying potential therapeutic targets with important clinical implications.

show abstract

ABD-Derived Protein Blockers of Human IL-17 Receptor A as Non-IgG Alternatives for Modulation of IL-17-Dependent Pro-Inflammatory Axis

Cited by 10 publications

References 55 publications

Targeting Human Thrombus by Liposomes Modified with Anti-Fibrin Protein Binders

Targeting Human Thrombus by Liposomes Modified with Anti-Fibrin Protein Binders

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Identification and functional analysis of long non‐coding RNAs in the synovial membrane of osteoarthritis patients

Contact Info

Product

Resources

About