Targeting QPCTL: An Emerging Therapeutic Opportunity.

Glutaminyl cyclases, including glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), primarily catalyze the cyclization of N-terminal glutamine or glutamate to pyroglutamate (pGlu). QPCTL, in particular, modifies the N-terminus of CD47, thereby regulating its interaction with signal-regulatory protein alpha (SIRPα) and modulating phagocytosis of tumor cells by immune cells. Additionally, QPCTL cyclizes the N-termini of CCL2, CCL7, and CX3CL1, influencing the tumor microenvironment and inflammatory responses in cancer and other disorders. Consequently, QPCTL is considered a valuable therapeutic target for several human diseases. However, the development of QPCTL inhibitors remains in its early stages. This perspective summarizes the structural features, catalytic mechanisms, and biological functions of QPCTL, along with its recent advances in small-molecule inhibitors. It provides valuable insights into the development of novel QPCTL inhibitors.