Computationally Designed Peptide Inhibitors of the Ubiquitin E3 Ligase SCF<sup>Fbx4</sup>

Lee, Junglim; Sammond, Deanne W.; Fiorini, Zeno; Saludes, Jonel P.; Resch, Michael G.; Hao, Bing; Wang, Wei; Yin, Hang; Liu, Xuedong

doi:10.1002/cbic.201200777

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…This approach is frequently the first validatation of PPI targetability, provides useful structural indicators for the design of nonpeptidic inhibitors, and can result in useful biochemical and cellular probes for chemical biology studies. Recent examples of this include a structure-based design of p53 transactivation domains (TAD) mimetics, and inhibitors of ubiquitin E3 ligase SCF Fbx4 …”

Section: Approaches For Hit Identification Of Ppi Modulatorsmentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

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Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein−protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

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Section: Approaches For Hit Identification Of Ppi Modulatorsmentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

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“…111 A computational approach has also led to the discovery of inhibitors of the ubiquitin E3 ligase-SCFFbx4 to control TRF1 degradation, a process involved in telomerase activity. 112…”

Section: In Silico Screeningmentioning

confidence: 99%

Modulating protein–protein interactions: the potential of peptides

2015

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Protein-protein interactions (PPIs) have emerged as important and challenging targets in chemical biology and medicinal chemistry. The main difficulty encountered in the discovery of small molecule modulators derives from the large contact surfaces involved in PPIs when compared with those that participate in protein-small molecule interactions. Because of their intrinsic features, peptides can explore larger surfaces and therefore represent a useful alternative to modulate PPIs. The use of peptides as therapeutics has been held back by their instability in vivo and poor cell internalization. However, more than 200 peptide drugs and homologous compounds (proteins or antibodies) containing peptide bonds are (or have been) on the market, and many alternatives are now available to tackle these limitations. This review will focus on the latest progress in the field, spanning from "lead" identification methods to binding evaluation techniques, through an update of the most successful examples described in the literature.

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“…In a similar approach, London et al developed a protocol that searches protein-protein interactions and identifies hot segments by comparing the calculated binding energy (using Rosetta software) of the fragments to the binding energy of the entire protein to the target [ 70 ]. The peptides derived from these protocol were shown to be able to inhibit a number of protein targets including TLR4 [ 71 ], ubiquitin E3 ligase SCF Fbx4 [ 52 ], and gankyrin-ATPase complex [ 72 ]. This protocol is available through the Peptiderive server [ 73 ] where starting from a protein-protein complex, a hot segment is suggested and if possible, is cyclized via addition of a disulfide bond or through N-to-C cyclization.…”

Section: Structure-guided Design Of Functional Peptidesmentioning

confidence: 99%

Design of Protein Segments and Peptides for Binding to Protein Targets

2022

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Recent years have witnessed a rise in methods for accurate prediction of structure and design of novel functional proteins. Design of functional protein fragments and peptides occupy a small, albeit unique, space within the general field of protein design. While the smaller size of these peptides allows for more exhaustive computational methods, flexibility in their structure and sparsity of data compared to proteins, as well as presence of noncanonical building blocks, add additional challenges to their design. This review summarizes the current advances in the design of protein fragments and peptides for binding to targets and discusses the challenges in the field, with an eye toward future directions.

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Computationally Designed Peptide Inhibitors of the Ubiquitin E3 Ligase SCF^Fbx4

Cited by 7 publications

References 41 publications

Modulators of Protein–Protein Interactions

Modulators of Protein–Protein Interactions

Modulating protein–protein interactions: the potential of peptides

Design of Protein Segments and Peptides for Binding to Protein Targets

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Computationally Designed Peptide Inhibitors of the Ubiquitin E3 Ligase SCFFbx4

Cited by 7 publications

References 41 publications

Modulators of Protein–Protein Interactions

Modulators of Protein–Protein Interactions

Modulating protein–protein interactions: the potential of peptides

Design of Protein Segments and Peptides for Binding to Protein Targets

Contact Info

Product

Resources

About

Computationally Designed Peptide Inhibitors of the Ubiquitin E3 Ligase SCF^Fbx4