Leishmanolysin (GP63) (GP63)

Leishmanolysin (GP63) is a major zinc-dependent metalloprotease and the most abundant surface glycoprotein found on Leishmania parasites. It functions as a critical virulence factor that facilitates the parasite's survival within both the sandfly vector and the human host's macrophages (McGwire et al., 2003, PubMed: 12626573). GP63 promotes infection by degrading host extracellular matrix components and inactivating the complement system, specifically converting C3b to iC3b to prevent parasite lysis while encouraging phagocytosis (Brittingham et al., 1995, PubMed: 7753026). Once inside the macrophage, GP63 cleaves and activates host protein tyrosine phosphatases like SHP-1, which suppresses pro-inflammatory signaling and the production of microbicidal reactive oxygen species (Gomez et al., 2009, PubMed: 19182813). Due to its multifaceted role in establishing and maintaining infection, GP63 is a primary target for the development of novel antileishmanial drugs and vaccines (Olivier et al., 2012, PubMed: 22848243). Current drug discovery efforts include identifying specific inhibitors, such as various zinc chelators and glycoside derivatives, that can disrupt its proteolytic activity without affecting host metalloproteinases (Chakrabarti et al., 2022, PubMed: 35593843).

Other names

Major surface proteaseMSPPromastigote surface proteasePSPGlycoprotein 63Promastigote surface endopeptidaseCell surface proteaseMajor surface glycoproteinZinc-dependent metalloproteinase GP63

Inhibition of the zinc-dependent proteolytic activity of GP63 to prevent host immune evasion, restore the host's pro-inflammatory response, and increase parasite susceptibility to complement-mediated lysis.