Identification of TAT-pQYP peptide ligands

• Grant number: 23/09168-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date until: September 01, 2023
• End date until: August 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Deborah Schechtman
• Grantee: Heloisa Espreafico Guelerman Ramos
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/06982-6 - Characterization and development of new modulators of the TrkA and PKMzeta pathways in inflammatory and chronic pain, AP.TEM

Abstract

Pain plays a key protective role in maintaining tissue integrity and homeostasis, but it is also involved in pathological processes that makes the search for pain treatments of great relevance. Among the mediators secreted when there is tissue damage, the nerve growth factor (NGF) plays a significant role in pain perception through its interaction with its receptor, the tropomyosin receptor kinase A (TrkA), expressed on the membrane of nociceptive neurons. This interaction can trigger different signaling pathways, including the propagation of signal to the central nervous system through the phosphorylation and activation of phospholipase C gamma (PLC5þ), which acts in a cascade that culminates in neuronal depolarization by activating the Transient Receptor Potential Cation Channel Vanilloid type 1 (TRPV1). Knowing that PLC5þ anchors to TrkA through the interaction between its SH2 domain and the phosphorylated Y785 (pY785) of TrkA, our group developed a peptide homologous to the region containing TrkA's pY785, coupled to a TAT carrier, named TAT-pQYP, which disrupts the anchoring of PLC5þ and thus inhibits its signaling, reducing the mechanical and thermal hypersensitivity generated by NGF. However, there are reports in the literature of other proteins that also interact with TrkA's pY785, such as CHK, or that also have SH2 domains similar to PLC5þ, suggesting that TAT-pQYP could also have affinity for other proteins, thereby modulating pain through different mechanisms or causing possible side effects. Thus, this project aims to determine other protein partners of our peptide through binding assays and mass spectrometry, and validate these targets and their role in pain signaling.