Β Catenin Puns

Journal Name: CNS & Neurological Disorders - Drug Targets

Formerly Current Drug Targets - CNS & Neurological Disorders

Volume 19 , Issue 1 , 2020

DOI : https://doi.org/10.2174/1871527319666200120143133

URL: https://www.eurekaselect.com/node/178451/article/neuronal-excitability-in-epileptogenic-zones-regulated-by-the-wnt-catenin-pathway

Starting from a 52 amino acid protein binding epitope, a bicyclic β‐hairpin structure was developed to bind the transcriptional coactivator β‐catenin. Our structure‐based design approach was supported by screening a focused library of bicyclic mimetics which was generated via late‐stage diversification. The most active bicyclic β‐hairpin shows cell‐penetration and inhibits Wnt signaling in a cell‐based assay.

Abstract

Protein complexes are defined by the three‐dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied for example, as inhibitors of protein–protein interactions (PPIs). Even though β‐sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure‐based design of β‐sheet mimetics targeting the intracellular protein β‐catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β‐catenin, a macrocyclic peptide was designed and its crystal structure in complex with β‐catenin obtained. Using this structure, we designed a library of bicyclic β‐sheet mimetics employing a late‐stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β‐catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β‐sheet‐mediated PPIs.

https://ift.tt/31vMAC5

Bicyclic peptidomimetics bind the transcriptional coactivator β‐catenin. A structure‐based design strategy has been applied to minimize a 52 amino acid binding motif into bicyclic 16‐mer β‐sheet mimetics. The biologically most active mimetic exhibits robust cellular uptake and inhibits Wnt signaling in a cell‐based assay, as reported by Tom N. Grossmann et al. in their Research Article (DOI: 10.1002/anie.202102082).

https://ift.tt/32wtk84

The sulfur‐coordinated organoiridium(III) complexes pbtIrSS and ppyIrSS , which contain C,N and S,S (dithione) chelating ligands, are found to inhibit breast cancer tumorigenesis and metastasis via targeting Wnt/β‐catenin signaling for the first time. Treatment with pbtIrSS and ppyIrSS induce the degradation of LRP6, thereby decreasing the protein levels of DVL2, β‐catenin and activated β‐catenin, resulting in downregulation of Wnt target genes CD44 and survivin. Additionally, pbtIrSS and ppyIrSS can suppress cell migration and invasion of breast cancer cells. Furthermore, both complexes show the ability to inhibit sphere formation and mediate stemness properties of breast cancer cells. Importantly, pbtIrSS exerts potent anti‐tumor and anti‐metastasis effects in mouse xenograft models through the blockage of Wnt/β‐catenin signaling. Taken together, our results indicate that pbtIrSS has great potential to be developed as a breast cancer therapeutic agent with a novel mechanism.

https://ift.tt/2HHbPek

Protein complexes are defined by the three‐dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied e.g. as inhibitors of protein‐protein interactions (PPIs). Even though β‐sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure‐based design of β‐sheet mimetics targeting the intracellular protein β‐catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β‐catenin, a macrocyclic peptide was designed and its crystal structure in complex with β‐catenin obtained. Using this structure, we designed a library of bicyclic β‐sheet mimetics employing a late‐stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β‐catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β‐sheet‐mediated PPIs.

https://ift.tt/31vMAC5