Drug Discovery Opinion

The leishmaniases are caused by protozoa transmitted by the bite of infected female sandflies. The disease has a variety of clinical manifestations: cutaneous forms which produce skin ulcers and can leave permanent disfigurement; mucocutaneous forms which can lead to partial or total destruction of the mucous membranes of the nose, mouth and throat cavities; and visceral forms which affect the internal organs and are often fatal. Pentavalent antimony, which is believed to work by inhibition of adenosine triphosphate synthesis, remains a first line treatment for the disease and preventing sandfly bites is currently the best form of prophylaxis since there are currently no vaccines against the disease. The last 10 years have seen a sharp increase in the number of recorded cases of leishmaniasis, with an estimated 2 million new cases each year. In many parts of the world, the parasite has developed resistance to antimony-based drugs and, although new treatments have been discovered and more are being tested, there is a real need for new therapies and for effective prophylaxis.

Following a bite by an infected sandfly, the parasites enter the blood stream and are ingested by macrophages. In all Leishmania species studied so far, the major surface protein GP63 acts as a virulence factor and is known to help the parasite to survive host immune mechanisms and aid cell invasion, although exactly how it achieves this was unclear. Researchers from McGill University have now shown that the GP63 metallo-protease activates a number of host protein tyrosine phosphatases. The activated protein tyrosine phosphatases then inhibit macrophage inflammatory immune responses through dephosphorylation of JAK/STAT and MAPK kinases. As well as SHP-1, which was already known to be activated by GP63, and whose activation leads to down-regulation of Janus kinase and mitogen activated protein kinase signalling, the team found that PTP1B and T-cell phosphatase are also activated by GP63. The proteolytic activation of SHP-1, PTP1B and T cell phosphatase was found to be mediated, in part, by a lipid raft–dependent mechanism. In vivo data in infected mice suggested that GP63-dependent modulation of PTP1B plays an important role in disease progression during the early, but not late, stages of the disease. The team hope that inhibiting GP63 could lead to the development of the first prophylactic treatment against leishmania infection.

The study is published in the September 29^th edition of Science Signaling.

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