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Study of new chemotherapeutic approaches for the treatment of leishmaniasis

Grant number: 05/04590-0
Support type:Regular Research Grants
Duration: May 01, 2006 - May 31, 2008
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Silvia Reni Bortolin Uliana
Grantee:Silvia Reni Bortolin Uliana
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leishmaniasis represents a group of diseases with multiple clinical presentations, some of which are mutilating or even fatal if untreated. The strategies for controlling the transmission of leishmaniasis are ineffective and this is reflected into the increasing world incidence with oubreaks spreading into new geographic areas. We have been investigating the leishmanicidal activity of three groups of compounds: terpenes, the antineoplastic drug tamoxifen and nitric oxide-donors. Terpenes are products of the isoprenoid biosynthetic pathway in plants and are present in a varity of food products and volatile oils, especially citrics. The antimicrobial and antitumoral acitivy of some terpenes was shown in several systems and seems to be dependent on the inhibition of the isoprenoid biosynthetic pathway. We have recently shown the antileishmanial activity of nerolidol in vitro and in vivo and its properties as an inhibitor of farnesyl pyrophosphate synthesis in Leishmania. We have also verified that the cyclic monoterpene limonene inhibits the growth of Leishmania in vitro and induces good therapeutic responses on experimentally infected mice. In mammals, limonene is metabolised to perillyl alcohol, perillyl aldehyde and finally perillic acid. These compounds are well absorbed by the gastrointestinal tract and have gone through phase I clinical tests for several types of cancer. Their antiparasitc properties are unknown. Results obtained so far with limonene in the treatment of murine experimental leishmaniasis warrant further studies aimed at understading the mechanisms of action of this terpene and testing limonene's derivatives for their antileishmanial activity and mode of action. This study should also improve our understanding of particular steps of the isoprenoid biosynthesis in these organisms. Tamoxifen is a synthetic triphenylethene derivative in clinical use for breast cancer treatment since 1971... (AU)