Rational design of TNFα binding proteins based on the <i>de novo</i> designed protein DS119

Zhu, Cheng; Zhang, Tao; Shen, Qi; Tang, Bo; Liang, Huanhuan; Lai, Luhua

doi:10.1002/pro.3029

Cited by 5 publications

(4 citation statements)

References 43 publications

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“…The common approach for computational design of interfaces is to build a full model of the complex. This model is used to evaluate whether the scaffold can accommodate the desired contacts while avoiding potential clashes in other parts of the protein and to assess the overall stability of the complex (see, e.g., Huang et al, 2007;Zhu et al, 2016). These designed templates can serve as a basis for a library, e.g., with random mutations (Baran et al, 2017) to find a tight binder.…”

Section: Discussionmentioning

confidence: 99%

Computational Design of Epitope-Specific Functional Antibodies

Nimrod

Fischman

Austin³

et al. 2018

Cell Reports

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Section: Discussionmentioning

confidence: 99%

Computational Design of Epitope-Specific Functional Antibodies

Nimrod

Fischman

Austin³

et al. 2018

Cell Reports

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“…A number of studies have used Bhot-spot-centric-design^that grafts hot-spot residues found in a naturally occurring protein complex to a designed interface, followed by computational sequence optimization for better side chain packing over the entire interface area ( Fig. 1a; Azoitei et al 2011;Fleishman et al 2011;Azoitei et al 2012Azoitei et al , 2014Whitehead et al 2012;Procko et al 2013Procko et al , 2014Berger et al 2016;Zhu et al 2016;Liu et al 2017;Strauch et al 2017;Chevalier et al 2017).…”

Section: Computational Ppi Designmentioning

confidence: 99%

Creation of artificial protein–protein interactions using α-helices as interfaces

2017

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Designing novel protein-protein interactions (PPIs) with high affinity is a challenging task. Directed evolution, a combination of randomization of the gene for the protein of interest and selection using a display technique, is one of the most powerful tools for producing a protein binder. However, the selected proteins often bind to the target protein at an undesired surface. More problematically, some selected proteins bind to their targets even though they are unfolded. Current state-of-the-art computational design methods have successfully created novel protein binders. These computational methods have optimized the non-covalent interactions at interfaces and thus produced artificial protein complexes. However, to date there are only a limited number of successful examples of computationally designed de novo PPIs. De novo design of coiled-coil proteins has been extensively performed and, therefore, a large amount of knowledge of the sequence-structure relationship of coiled-coil proteins has been accumulated. Taking advantage of this knowledge, de novo design of inter-helical interactions has been used to produce artificial PPIs. Here, we review recent progress in the in silico design and rational design of de novo PPIs and the use of α-helices as interfaces.

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“…Zhu et al have reported several rationally designed proteins that directly bound to TNF-α. They grafted three key residues from a virus viral 2L protein to a de novo designed small protein DS119, and then optimized their residues at the interface, which provided some small proteins that bind TNF-α with sub-micromolar affinities (Zhu et al, 2016 ). Other than small proteins, bicyclic peptides and helical peptides were also designed as peptidic antagonists of TNF-α (Lian et al, 2013 ; Zhang et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-α Inhibitors

et al. 2018

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Tumor necrosis factor-α (TNF-α) plays a pivotal role in inflammatory response. Dysregulation of TNF can lead to a variety of disastrous pathological effects, including auto-inflammatory diseases. Antibodies that directly targeting TNF-α have been proven effective in suppressing symptoms of these disorders. Compared to protein drugs, small molecule drugs are normally orally available and less expensive. Till now, peptide and small molecule TNF-α inhibitors are still in the early stage of development, and much more efforts should be made. In a previously study, we reported a TNF-α inhibitor, EJMC-1 with modest activity. Here, we optimized this compound by shape screen and rational design. In the first round, we screened commercial compound library for EJMC-1 analogs based on shape similarity. Out of the 68 compounds tested, 20 compounds showed better binding affinity than EJMC-1 in the SPR competitive binding assay. These 20 compounds were tested in cell assay and the most potent compound was 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide (S10) with an IC50 of 14 μM, which was 2.2-fold stronger than EJMC-1. Based on the docking analysis of S10 and EJMC-1 binding with TNF-α, in the second round, we designed S10 analogs, purchased seven of them, and synthesized seven new compounds. The best compound, 4e showed an IC50-value of 3 μM in cell assay, which was 14-fold stronger than EJMC-1. 4e was among the most potent TNF-α organic compound inhibitors reported so far. Our study demonstrated that 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide analogs could be developed as potent TNF-α inhibitors. 4e can be further optimized for its activity and properties. Our study provides insights into designing small molecule inhibitors directly targeting TNF-α and for protein–protein interaction inhibitor design.

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Rational design of TNFα binding proteins based on the de novo designed protein DS119

Cited by 5 publications

References 43 publications

Computational Design of Epitope-Specific Functional Antibodies

Computational Design of Epitope-Specific Functional Antibodies

Creation of artificial protein–protein interactions using α-helices as interfaces

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-α Inhibitors

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