Open AccessMiransertib (ARQ 092), an orally-available, selective Akt inhibitor is effective against Leishmania
Author(s) -
Devki Nandan,
Naixin Zhang,
Yi Yu,
Brian Schwartz,
Stella Chen,
Peter E. Kima,
Neil E. Reiner
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0206920
Subject(s) - visceral leishmaniasis , leishmania , leishmaniasis , amastigote , leishmania donovani , protein kinase b , miltefosine , pharmacology , cutaneous leishmaniasis , pi3k/akt/mtor pathway , biology , immunology , medicine , phosphorylation , signal transduction , parasite hosting , biochemistry , world wide web , computer science
Leishmaniasis is amongst the most important neglected diseases, afflicting more than 12 million people in 88 countries. There is an urgent need for safe orally bioavailable and cost-effective drugs for the treatment of leishmaniasis. It has recently been shown that Leishmania activates host macrophage serine/threonine kinase Akt, to promote survival of both parasites and infected cells. Here, we sought to evaluate a compound, Miransertib (ARQ 092), an orally bioavailable and selective allosteric Akt inhibitor currently in clinical trials for patients with PI3K/Akt-driven tumors or Proteus syndrome. Miransertib was tested against Leishmania donovani and Leishmania amazonensis , causative agents of visceral and cutaneous leishmaniasis, respectively. Cultured promastigotes were susceptible to Miransertib. In addition, Miransertib was markedly effective against intracellular amastigotes of L . donovani or L . amazonensis -infected macrophages. Miransertib also enhanced mTOR dependent autophagy in Leishmania -infected macrophages, which may represent one mechanism of Miransertib-mediated killing of intracellular Leishmania . Whereas parasite clearance in the spleen of mice infected with L . donovani and treated with Miransertib was comparable to that when treated with miltefosine, Miransertib caused a greater reduction in the parasite load in the liver. In the cutaneous leishmaniasis infection model, lesions were reduced by 40% as compared to mock treated mice. Together, these results provide direct evidence to support the conclusion that Miransertib is an excellent lead compound for the development of a new oral drug therapy for visceral and cutaneous leishmaniasis.