Miransertib (ARQ 092), an orally-available, selective Akt inhibitor is effective against Leishmania

• DOI: 10.1371/journal.pone.0206920
• Publication Date: 2018-11-06T13:39:24Z
• Authors: Devki Nandan; Naixin Zhang; Yi Yu; Brian Schwartz; Stella Chen; Peter E. Kima; Neil E. Reiner
• Keywords: Amastigote; Miltefosine

Leishmaniasis is amongst the most important neglected diseases, afflicting more than 12 million people in 88 countries. There an urgent need for safe orally bioavailable and cost-effective drugs treatment of leishmaniasis. It has recently been shown that Leishmania activates host macrophage serine/threonine kinase Akt, to promote survival both parasites infected cells. Here, we sought evaluate a compound, Miransertib (ARQ 092), selective allosteric Akt inhibitor currently clinical trials patients with PI3K/Akt-driven tumors or Proteus syndrome. was tested against donovani amazonensis, causative agents visceral cutaneous leishmaniasis, respectively. Cultured promastigotes were susceptible Miransertib. In addition, markedly effective intracellular amastigotes L. amazonensis-infected macrophages. also enhanced mTOR dependent autophagy Leishmania-infected macrophages, which may represent one mechanism Miransertib-mediated killing Leishmania. Whereas parasite clearance spleen mice treated comparable when miltefosine, caused greater reduction load liver. leishmaniasis infection model, lesions reduced by 40% as compared mock mice. Together, these results provide direct evidence support conclusion excellent lead compound development new oral drug therapy