Development of Novel Therapeutics for Neglected Tropical Disease Leishmaniasis
Technical Report,30 Sep 2017,29 Sep 2018
U.S. Naval Medical Research Unit No. 6 (NAMRU-6) Lima Peru
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Infections caused by protozoan parasites of the genus Leishmania include cutaneous CL, mucosal ML and visceral leishmaniasis VL. Over 12 million people are currently suffering from leishmaniasis, and approximately 2 million new cases occur annually, making it a major global health problem and WHO designated neglected tropical disease NTD. Recently, CL has been seen in all branches of the US military and among DOD contractors returning from Leishmania-endemic countries such as Iraq and Afghanistan. Current widely used treatment for all forms of leishmaniasis including CL involves multiple injections of antimonial drugs GlucantimeTM or PentostamTM for 20 days or more. Therefore, this treatment has poor compliance, numerous adverse effects including death and is also not approved by the FDA therefore requiring use under IND in the US. Furthermore, in immunocompromised individuals antimonial treatment is associated with relapses. Other antileishmanial treatments currently under development do not offer new alternatives because they are either reformulations or combinations of existing drugs. Hence, there is pressing need for novel drugs for leishmaniasis. Our team is interested in discovering novel drugs to treat leishmaniasis from natural products. Work from our recently completed NIH-funded project has led to the discovery of antileishmanial molecules from the plant Pentalinon andrieuxii, which has been used by Mayan traditional healers for CL for many years. We have identified six sterols, including a novel sterol, pentalinosterol PEN, with broad-spectrum activity against Leishmania species that cause CL and visceral leishmaniasis VL. The synthesis of PEN has been established and methods for large scale synthesis of other active molecules are under development PCT Int. App. WO 2012145734A1. Our preliminary studies show that synthetic PEN sPEN is safe and more potent than antimonials SSG in the treatment of CL and VL in animal models.
- Medicine and Medical Research