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Structural Biology of the TNF? Antagonists Used in the Treatment of Rheumatoid Arthritis.

ABSTRACT: The binding of the tumor necrosis factor ? (TNF?) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are anti-TNF? agents. These drugs block TNF? from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNF?-TNF? antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNF? blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNF?. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNF? antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNF? for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNF? plays an important role in pathogenesis.

SUBMITTER: Lim H

PROVIDER: S-EPMC5877629 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis.

Lim Heejin H Lee Sang Hyung SH Lee Hyun Tae HT Lee Jee Un JU Son Ji Young JY Shin Woori W Heo Yong-Seok YS

International journal of molecular sciences 20180307 3

The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflam ...[more]

PMID: 29518978

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Project description:In 15 patients with rheumatoid arthritis the baseline expression (t=0) of type I IFN-regulated genes was determined in peripheral blood cells (PAXgene) using cDNA-microarrays and compared to levels one month after (t=1) anti-TNF treatment (infliximab). Therefore, we used 43K cDNA microarrays from the Stanford Functional Genomics Facility (http://microarray.org/sfgf/) printed on aminosilane-coated slides containing ~20.000 unique genes. Only one batch of arrays was used for all experiments. First DNA spots were UV-cross linked to the slide using 150-300 mJoules. Sample preparation and microarray hybridization were performed as described previously (1,2). Data storage and filtering was performed using the Stanford Microarray Database (http://genome-www5.stanford.edu//) as described previously. 1. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM et al.: Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 2007, 66: 1008-1014. 2. van der Pouw Kraan TC, van Baarsen LG, Rustenburg F, Baltus B, Fero M, Verweij CL: Gene expression profiling in rheumatology. Methods Mol Med 2007, 136: 305-327. Abbreviations: - Bnrs are the different patients analyzed - PAX or Paxgene indicates the total RNA was isolated from peripheral blood obtained in PAXgene tubes - CRS: common reference sample: We made a common reference that consisted of a mixture of mRNAs isolated from 11 different cell lines (Perou CM, Jeffrey SS, van de RM et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A. 1999; 96:9212-9217) supplemented with RNA from rheumatoid synovial tissue, fibroblasts, and activated peripheral blood mononuclear cells (PBMCs). - PMT: photomultiplier tube: the sensitivity/intensity of the scanner can be adjusted to prevent spot saturation. Compound Based Treatment: anti-TNF (infliximab)

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Structural Biology of the TNF? Antagonists Used in the Treatment of Rheumatoid Arthritis.

Publications

Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis.

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