scholarly journals A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniel J. Lightwood ◽  
Rebecca J. Munro ◽  
John Porter ◽  
David McMillan ◽  
Bruce Carrington ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Protein Protein Interactions ◽  
Human Tumour ◽  
Complex Crystal Structure ◽  
Human Tumour Necrosis Factor ◽  
Complex Crystal ◽  
Necrosis Factor

AbstractWe have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer–small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF–TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein–protein interactions.

Elucidating Protein-protein Interactions Through Computational Approaches and Designing Small Molecule Inhibitors Against them for Various Diseases

2018 ◽  
Vol 18 (20) ◽  
pp. 1719-1736 ◽  
Author(s):  
Sharanya Sarkar ◽  
Khushboo Gulati ◽  
Manikyaprabhu Kairamkonda ◽  
Amit Mishra ◽  
Krishna Mohan Poluri
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Computational Techniques ◽  
Protein Protein Interactions ◽  
Computational Tools ◽  
Computational Approaches ◽  
Protein Protein Interaction ◽  
Wide Range ◽  
Therapeutic Measures

Background: To carry out wide range of cellular functionalities, proteins often associate with one or more proteins in a phenomenon known as Protein-Protein Interaction (PPI). Experimental and computational approaches were applied on PPIs in order to determine the interacting partners, and also to understand how an abnormality in such interactions can become the principle cause of a disease. Objective: This review aims to elucidate the case studies where PPIs involved in various human diseases have been proven or validated with computational techniques, and also to elucidate how small molecule inhibitors of PPIs have been designed computationally to act as effective therapeutic measures against certain diseases. Results: Computational techniques to predict PPIs are emerging rapidly in the modern day. They not only help in predicting new PPIs, but also generate outputs that substantiate the experimentally determined results. Moreover, computation has aided in the designing of novel inhibitor molecules disrupting the PPIs. Some of them are already being tested in the clinical trials. Conclusion: This review delineated the classification of computational tools that are essential to investigate PPIs. Furthermore, the review shed light on how indispensable computational tools have become in the field of medicine to analyze the interaction networks and to design novel inhibitors efficiently against dreadful diseases in a shorter time span.

Rational Design of Selective Small-Molecule Inhibitors for β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interactions

2015 ◽  
Vol 137 (38) ◽  
pp. 12249-12260 ◽  
Author(s):  
Logan R. Hoggard ◽  
Yongqiang Zhang ◽  
Min Zhang ◽  
Vanja Panic ◽  
John A. Wisniewski ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Protein Interactions ◽  
Rational Design ◽  
Small Molecule Inhibitors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Protein Protein Interactions ◽  
Catenin B

scholarly journals Correction: State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

2015 ◽  
Vol 44 (22) ◽  
pp. 8375-8375 ◽  
Author(s):  
Chunquan Sheng ◽  
Guoqiang Dong ◽  
Zhenyuan Miao ◽  
Wannian Zhang ◽  
Wei Wang
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
State Of The Art ◽  
Protein Protein Interactions

Correction for ‘State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors’ by Chunquan Sheng et al., Chem. Soc. Rev., 2015, DOI: 10.1039/c5cs00252d.

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

scholarly journals Small-Molecule Inhibitors That Target Protein-Protein Interactions in the RAD51 Family of Recombinases

ChemMedChem ◽  
2014 ◽  
Vol 10 (2) ◽  
pp. 296-303 ◽  
Author(s):  
Duncan E. Scott ◽  
Anthony G. Coyne ◽  
Ashok Venkitaraman ◽  
Tom L. Blundell ◽  
Chris Abell ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Target Protein ◽  
Protein Protein Interactions
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