scholarly journals Evaluation of Computationally Designed Peptides against TWEAK, a Cytokine of the Tumour Necrosis Factor Ligand Family

2021 ◽  
Vol 22 (3) ◽  
pp. 1066
Author(s):  
Miriam Badia-Villanueva ◽  
Sira Defaus ◽  
Ruben Foj ◽  
David Andreu ◽  
Baldo Oliva ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Protein Interactions ◽  
In Silico ◽  
Tumour Necrosis ◽  
In Vitro Assays ◽  
Physical Interaction ◽  
Vitro Assay ◽  
Starting Point ◽  
Necrosis Factor

The tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumour necrosis factor ligand family and has been shown to be overexpressed in tumoral cells together with the fibroblast growth factor–inducible 14 (Fn14) receptor. TWEAK-Fn14 interaction triggers a set of intracellular pathways responsible for tumour cell invasion and migration, as well as proliferation and angiogenesis. Hence, modulation of the TWEAK-Fn14 interaction is an important therapeutic goal. The targeting of protein-protein interactions by external agents, e.g., drugs, remains a substantial challenge. Given their intrinsic features, as well as recent advances that improve their pharmacological profiles, peptides have arisen as promising agents in this regard. Here, we report, by in silico structural design validated by cell-based and in vitro assays, the discovery of four peptides able to target TWEAK. Our results show that, when added to TWEAK-dependent cellular cultures, peptides cause a down-regulation of genes that are part of TWEAK-Fn14 signalling pathway. The direct, physical interaction between the peptides and TWEAK was further elucidated in an in vitro assay which confirmed that the bioactivity shown in cell-based assays was due to the targeting of TWEAK. The results presented here are framed within early pre-clinical drug development and therefore these peptide hits represent a starting point for the development of novel therapeutic agents. Our approach exemplifies the powerful combination of in silico and experimental efforts to quickly identify peptides with desirable traits.

Plasma Inhibitory Activity against Tumour Necrosis Factor in Fulminant Hepatic Failure

1996 ◽  
Vol 90 (1) ◽  
pp. 77-80 ◽  
Author(s):  
Helen M. Keane ◽  
Nick Sheron ◽  
John Goka ◽  
Robin D. Hughes ◽  
Roger Williams
Keyword(s):  
Tumour Necrosis Factor ◽  
Normal Control ◽  
Fulminant Hepatic Failure ◽  
Hepatic Failure ◽  
Tumour Necrosis ◽  
Neutralization Capacity ◽  
Control Subjects ◽  
Significant Difference ◽  
Necrosis Factor

1. Soluble tumour necrosis factor receptors released into the circulation inhibit the effects of excess tumour necrosis factor-α and represent an important protective response. 2. In this study we have measured the levels of tumour necrosis factor and soluble tumour necrosis factor receptors p55 and p75 in the plasma of 10 patients with fulminant hepatic failure and 10 healthy control subjects. The capacity of the plasmas at varying dilutions to inhibit the biological activity of 1000 pg/ml of recombinant tumour necrosis factor in a tumour necrosis factor cytotoxicity assay in vitro was also determined. 3. The mean plasma levels of tumour necrosis factor in patients with fulminant hepatic failure (48.4 ± 10.9 pg/ml) were significantly increased compared with normal control subjects (6.1 ± 1.04 pg/ml, P < 0.01). Plasma soluble tumour necrosis factor receptors p55 and p75 were also significantly elevated in patients with fulminant hepatic failure (18.16 ± 9.94 ng/ml and 16.06 ± 9.93 ng/ml respectively) when compared with normal control subjects (1.28 ± 0.24 ng/ml and 1.62 ± 0.91 ng/ml, P < 0.001). 4. Fulminant hepatic failure plasma had a much lower capacity to inhibit tumour necrosis factor bioactivity in vitro, with a statistically significant difference between the inhibitory capacity of the fulminant hepatic failure and normal plasma seen at plasma dilutions of 1:5 and 1:20 (P < 0.05). 5. The reduced tumour necrosis factor neutralization capacity observed in fulminant hepatic failure, despite the increased levels of soluble tumour necrosis factor receptors, suggests enhanced susceptibility to the potential deleterious effects of tumour necrosis factor in fulminant hepatic failure.

scholarly journals Tumour necrosis factor-α induces hyperreactivity in tracheal smooth muscle of the guinea-pig in vitro

1998 ◽  
Vol 12 (1) ◽  
pp. 45-49 ◽  
Author(s):  
H-J. Pennings ◽  
K. Kramer ◽  
A. Bast ◽  
W.A. Buurman ◽  
E.F.M. Wouters
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Tracheal Smooth Muscle ◽  
Factor I ◽  
Necrosis Factor

scholarly journals Association of a RING finger protein with the cytoplasmic domain of the human type-2 tumour necrosis factor receptor

1995 ◽  
Vol 309 (3) ◽  
pp. 825-829 ◽  
Author(s):  
H Y Song ◽  
D B Donner
Keyword(s):  
Tumour Necrosis Factor ◽  
Hybrid System ◽  
Tumour Necrosis ◽  
Ring Finger ◽  
Tnf Receptor ◽  
Intracellular Domain ◽  
Two Hybrid ◽  
Necrosis Factor

A human gene encoding a protein that specifically binds to the intracellular domain of the 75 kDa type-2 tumour necrosis factor (TNF) receptor (TNFR-2IC) has been identified using the yeast-based two-hybrid system. The N-terminal half of the TNF receptor-associated protein (TRAP) contains RING finger and zinc finger motifs often found in DNA-binding proteins including transcription factors. The 2.4 kb TRAP mRNA was barely detectable, if present at all, in lung, and variably expressed in heart, liver, placenta, brain, skeletal muscle, kidney and the pancreas; interestingly, the TRAP was more highly expressed in transformed cell lines than in normal tissues. This observation may be consistent with a role for this TRAP in promoting or regulating cellular proliferation. After in vitro transcription/translation and 35S labelling the TRAP was precipitated using a fusion protein consisting of glutathione S-transferase and the intracellular domain of TNFR-2 (TNFR-2IC), which showed that the two proteins directly interact in a mammalian cell-free system and also that identification of the TRAP was not an artifact of the two-hybrid system. By using truncated TNFR-2ICs for in vitro precipitation of 35S-TRAP, it was shown that the C-terminal half of the TNFR-2IC contains the domain necessary for interaction with TRAP. The TRAP identified in the present study shares considerable homology with, and may be the human homologue of, a mouse protein, TNF receptor-associated factor 2 (TRAF2), that binds mouse TNFR-2.

Antiviral effects of recombinant tumour necrosis factor in vitro

Nature ◽  
1986 ◽  
Vol 323 (6091) ◽  
pp. 816-819 ◽  
Author(s):  
J. Mestan ◽  
W. Digel ◽  
S. Mittnacht ◽  
H. Hillen ◽  
D. Blohm ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Antiviral Effects ◽  
Necrosis Factor
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