A new class of supramolecular ligands stabilizes 14-3-3 protein–protein interactions by up to two orders of magnitude

2019 ◽  
Vol 55 (1) ◽  
pp. 111-114 ◽  
Author(s):  
A. Gigante ◽  
J.-N. Grad ◽  
J. Briels ◽  
M. Bartel ◽  
D. Hoffmann ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
New Class

Identification of novel non-natural supramolecular ligands as stabilizers of 14-3-3ζ protein–protein interactions.

scholarly journals Discovery, development and application of drugs targeting BCL-2 pro-survival proteins in cancer

2021 ◽  
Author(s):  
Erinna F. Lee ◽  
W. Douglas Fairlie
Keyword(s):  
Structural Biology ◽  
Protein Interactions ◽  
Basic Science ◽  
Great Success ◽  
Protein Protein Interactions ◽  
New Class ◽  
Success Stories ◽  
History Of ◽  
Approved Drugs ◽  
Close Relatives

The discovery of a new class of small molecule compounds that target the BCL-2 family of anti-apoptotic proteins is one of the great success stories of basic science leading to translational outcomes in the last 30 years. The eponymous BCL-2 protein was identified over 30 years ago due to its association with cancer. However, it was the unveiling of the biochemistry and structural biology behind it and its close relatives’ mechanism(s)-of-action that provided the inspiration for what are now known as ‘BH3-mimetics’, the first clinically approved drugs designed to specifically inhibit protein–protein interactions. Herein, we chart the history of how these drugs were discovered, their evolution and application in cancer treatment.

Multivalent peptides displayed on OEGMA-based copolymers for the modulation of protein–protein interactions

2015 ◽  
Vol 6 (45) ◽  
pp. 7862-7870 ◽  
Author(s):  
Yujie Li ◽  
Tao Li ◽  
Jinghui Wang ◽  
Xiaojia Bao ◽  
Yibing Zhao ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Peptide Conjugates ◽  
New Class ◽  
Multiple Copies

We report a new class of copolymer–peptide conjugates which exploits the comb-shaped pOEGMA as a polymeric backbone, into which multiple copies of peptide chains that can modulate intracellular p53–Mdm2 or p53–Mdm4 protein interactions are incorporated.

Genetically encoded selective cross-linkers and emerging applications

2020 ◽  
Vol 48 (4) ◽  
pp. 1807-1817
Author(s):  
Haiyan Ren
Keyword(s):  
Protein Interactions ◽  
Unnatural Amino Acids ◽  
Protein Complexes ◽  
Living Cells ◽  
Cross Linking ◽  
Protein Protein Interactions ◽  
New Class ◽  
Selective Reaction ◽  
Biological Studies ◽  
Lower Background

There has been a large amount of interest in the development of genetically encoded cross-linkers that target functional groups naturally present in cells. Recently, a new class of unnatural amino acids that specifically react with target residues were developed and genetically incorporated. The selective reaction shows higher cross-linking efficiency, lower background and predictable cross-linking sites. It has been applied to enhance protein/peptide stability, pinpoint protein–protein interactions, stabilize protein complexes, engineer covalent protein inhibitors, identify phosphatases in living cells, etc. These new covalent linkages provide excellent new tools for protein engineering and biological studies. Their applications in biotherapy will provide considerable opportunities for innovating and improving biomolecular medicines.

scholarly journals AApeptides as a New Class of Peptidomimetics to Regulate Protein-Protein Interactions

10.5772/38829 ◽  
2012 ◽  
Author(s):  
Youhong Niu ◽  
Yaogang Hu ◽  
Rongsheng E. ◽  
Xiaolong Li ◽  
Haifan Wu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
New Class ◽  
Regulate Protein

scholarly journals Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3509
Author(s):  
Matteo Mori ◽  
Ettore Gilardoni ◽  
Luca Regazzoni ◽  
Alessandro Pedretti ◽  
Diego Colombo ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Malignant Tumors ◽  
Uv Spectroscopy ◽  
Sh2 Domain ◽  
Significant Activity ◽  
Protein Protein Interactions ◽  
New Class ◽  
Mechanism Of Interaction ◽  
The Relationship ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction.

ChemInform Abstract: AApeptides as a New Class of Peptidomimetics to Regulate Protein-Protein Interactions

ChemInform ◽  
2013 ◽  
Vol 44 (29) ◽  
pp. no-no
Author(s):  
Youhong Niu ◽  
Yaogang Hu ◽  
Rongsheng E. Wang ◽  
Xiaolong Li ◽  
Haifan Wu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
New Class ◽  
Regulate Protein

P3-295: Breaking protein-protein interactions: A combined chemical and computational approach to develop a new class of protein aggregation inhibitors

2009 ◽  
Vol 5 (4S_Part_14) ◽  
pp. P429-P430
Author(s):  
Isabella Graef ◽  
Mamoun M. Alhamadsheh ◽  
Alexandra Esteras-Chopo ◽  
Kim Branson ◽  
Mohua Bose ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Interactions ◽  
Computational Approach ◽  
Protein Protein Interactions ◽  
New Class ◽  
Aggregation Inhibitors

scholarly journals Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics

2021 ◽  
Vol 8 ◽  
Author(s):  
Mahdi Hassankalhori ◽  
Giovanni Bolcato ◽  
Maicol Bissaro ◽  
Mattia Sturlese ◽  
Stefano Moro
Keyword(s):  
Molecular Dynamics ◽  
Molecular Recognition ◽  
Protein Interactions ◽  
Binding Mode ◽  
Structural Features ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
New Class ◽  
Macrocyclic Peptides ◽  
Simulation Time

Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide—from a novel library of 8,988 sub-kilodalton macrocyclic peptides—in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle–protein molecular recognition studies.

scholarly journals Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting its Protein-Protein Interactions

2020 ◽  
Author(s):  
S. Bobone ◽  
L. Pannone ◽  
B. Biondi ◽  
M. Solman ◽  
E. Flex ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Central Target ◽  
New Class ◽  
Pathogenic Variants ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Multiple Signaling

AbstractWe developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in multiple signaling pathways and a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket, but lack specificity or are ineffective on disease-associated SHP2 mutants. Based on the consideration that pathogenic lesions cause signaling hyperactivation due to increased SHP2 association with cognate proteins, we developed peptide-based molecules with low nM affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation and an affinity for pathogenic variants of SHP2 up to 20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool to investigate the role of protein-protein interactions in the function of SHP2.

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