Table 1.
Blockers of PDZ-dependent interactions with therapeutic applications.
| Peptide/Inhibitor | PDZ-Dependent Interaction (PDZbm) |
Function of the PDZ-Dependent Interaction | Inhibitor Function |
Study Phase | Disease | Reference |
|---|---|---|---|---|---|---|
| Peptide Pen-N3 * | DVL2-PDZ: Frizzled (Internal PDZbm) (KWYGW) |
DVL facilitates Wnt signal, which leads to activation of b-catenin and T cell factor (TCF)-dependent transcription of developmental genes and genes associated with tumorigenesis | Inhibits canonical Wnt | Commercial: MERCK | Cancer | [35] |
| Tat-P4-(C5)2 * | PICK1-PDZ1: GluA2 (HWLKV) |
PICK1 regulates PKC-dependent phosphorylation of S880 of AMPAR Glu A2 subunit in trafficking and plasticity | Interferes with excessive glutamate receptor transmission in pain; disrupts the interaction of PICK1 with AMPARs | Preclinic, in vivo | Neuropathic pain | [36] |
| 3-hydroxymethylindole ** | MAGI3-PDZ2: PTEN (YKQTSV) |
Prevents PTEN recruitment to the plasma membrane and allows full activation of PKB | Blocks tumorigenic processes | Preclinic, in vitro | Cancer | [37] |
| NA-1 * | PDS-95-PDZ1: GluN2B (tSXV) |
GluN2B activates nNOs in association with PSD95, promoting excitotoxicity in ischemic stroke | Inhibits neuronal excitotoxicity; penetrates the blood–brain barrier and interferes with GluN2B intersctions | Clinic, phase III | Ischemic stroke | [33,38] |
| Synthetic peptide: FVGSSSGHTSTTL * | NHERF1-CXCR2 (STTL) |
Neutrophil migration in exacerbated inflammation | Proposed to be used in exacerbated inflammatory-related diseases | In vitro | Excessive neutrophil recruitment, tumorigenesis. | [39] |
| PDZ1i ** (CGSDKEϕϕV)2 * |
Syntenin-CD6 (ISAA) |
T cell activation and proliferation in autoimmune diseases: MS, EAE | Proposed to be used in autoimmune diseases | Theoretical | Autoimmune diseases | [40,41,42,43] |
| PDZ1i ** (CGSDKEϕϕV)2 * |
Syntenin-IL-5Ra (DSVF) |
Eosinophil differentiation and survival in severe asthma | Proposed to be used in severe eosinophilic asthma | Theoretical | Severe eosinophilic asthma | [40,41,44,45] |
| To be designed. There is an inhibitor for PDZ1 and 3 domains but not for PDZ4. |
Scrib-p22phox (DEVV) |
ROS production in macrophages to destroy pathogens; probably exacerbated hypertension, Alzheimer’s and Parkinson’s diseases | Proposed to be used in hypertension, Alzheimer’s and Parkinson’s diseases | Theoretical | Hypertension, Alzheimer’s and Parkinson’s diseases | [46,47,48,49] |
* Peptide; ** Small molecule.