1. A PDZ Protein MDA-9/Syntenin: As a Target for Cancer Therapy
Yongsheng Yu, Shuangdi Li, Kai Wang, Xiaoping Wan Comput Struct Biotechnol J. 2019 Jan 8;17:136-141. doi: 10.1016/j.csbj.2019.01.002. eCollection 2019.
Melanoma differentiation-associated gene 9 (MDA-9)/Syntenin is a multidomain PDZ protein and identified as a key oncogene in melanoma initially. This protein contains a unique tandem PDZ domain architecture (PDZ1 and PDZ2 spaced by a 4-amino acid linker), an N-terminal domain (NTD) that is structurally uncharacterized and a short C-terminal domain (CTD). The PDZ1 domain is regarded as the PDZ signaling domain while PDZ2 served as the PDZ superfamily domain. It has various cellular roles by regulating many of major signaling pathways in numerous cancertypes. Through the use of novel drug design methods, such as dimerization and unnatural amino acid substitution of inhibitors in our group, the protein may provide a valuable therapeutic target. The objective of this review is to provide a current perspective on the cancer-specific role of MDA-9/Syntenin in order to explore its potential for cancer drug discovery and cancer therapy.
2. PDZ1 inhibitor peptide protects neurons against ischemia via inhibiting GluK2-PSD-95-module-mediated Fas signaling pathway
Xiao-Hui Yin, Jing-Zhi Yan, Guo Yang, Li Chen, Xiao-Feng Xu, Xi-Ping Hong, Shi-Liang Wu, Xiao-Yu Hou, GuangYi Zhang Brain Res. 2016 Apr 15;1637:64-70. doi: 10.1016/j.brainres.2016.02.019. Epub 2016 Feb 15.
Respecting the selective inhibition of peptides on protein-protein interactions, they might become potent methods in ischemic stroke therapy. In this study, we investigated the effect of PDZ1 inhibitor peptide on ischemic neuron apoptosis and the relative mechanism. Results showed that PDZ1 inhibitor peptide, which significantly disrupted GluK2-PSD-95 interaction, efficiently protected neuron from ischemia/reperfusion-induced apoptosis. Further, PDZ1 inhibited FasL expression, DISC assembly and activation of Caspase 8, Bid, Caspase 9 and Caspase 3 after global brain ischemia. Based on our previous report that GluK2-PSD-95 pathway increased FasL expression after global brain ischemia, the neuron protection effect of PDZ1 inhibitor peptide was considered to be achieved by disrupting GluK2-PSD-95 interaction and subsequently inhibiting FasL expression and Fas apoptosis pathway.
3. Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95
Jie Zang, Fei Ye, Sara M Ø Solbak, Lars J Høj, Mingjie Zhang, Anders Bach ChemMedChem. 2021 Mar 18;16(6):949-954. doi: 10.1002/cmdc.202000865. Epub 2020 Dec 30.
Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by 1 H,15 N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.
