- A novel target mechanism by which STAP-2 is involved in the initiation of TCR signaling through the formation of a ternary complex with LCK and CD3ζ.
Background and Technology
Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains a pleckstrin homology (PH), Src homology 2 (SH2)-like domains, and proline-rich regions in its C-terminal. STAP-2 belongs to a family of STAP adaptor proteins and plays a crucial role in a variety of cellular signal transduction pathways by interacting with signaling or transcriptional molecules. STAP-2, in particular, regulates both the innate and adaptive immune systems.
We found that the new molecular interactions between STAP-2 and TCR signaling molecules, LCK and CD3ζ, upstream of ZAP-70. TCR signaling is started when CD3ζ is phosphorylated by LCK through STAP-2 interaction. We designed new small peptides to inhibit the molecular interactions. One of the peptides with cell-penetrating peptide (CPP) inhibited the STAP-2 interaction and the TCR-induced IL-2 production and T-cell proliferation (in vitro) and improved the pathological score in EAE model mice (in vivo).
Reference and Patent
Tadashi MATSUDA, Prof.
Department of Immunology, Graduate School of Pharmaceutical Sciences
Current Stage and Next Step
- The immunosuppressive effects of the peptide we designed and their mechanisms have been demonstrated in vitro and in vivo as the result of our academic research. No toxicity of this peptide has been observed in our previous cell and animal studies. Binding assay and structural analysis are ongoing.
- The next step will require lead peptide optimization and CPP design. Small or medium molecule designs based on the peptide may be possible.
- At this time, there is not enough data on the safety and PK / PD of the peptide.
We are looking for partners to further develop the drug candidate and will be happy to discuss partnership schemes and feasibility study procedures in the project.
Product No. BK-04110