New approaches to combination chemotherapy for human leishmaniasis

• Grant number: 12/51018-4
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2012
• End date: September 30, 2014
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Agreement: University of York
• Principal Investigator: Silvia Reni Bortolin Uliana
• Grantee: Silvia Reni Bortolin Uliana
• Principal researcher abroad: Deborah F. Smith
• Institution abroad: University of York, England
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 11/20484-7 - Tamoxifen in the treatment of leishmaniasis: evaluation of efficacy in combination therapy schemes and study of the antileishmanial mechanism of action, AP.R

Abstract

Human leishmaniasis is an endemic disease distributed in tropical and subtropical regions of the world with an estimated 2 million new cases each year. The treatment of all clinical forms of leishmaniasis relies on costly parenteral administered drugs with multiple undesirable effects. Moreover, the first line drugs are becoming ineffective due to the proliferation of resistant parasites. The discovery of new alternative drugs and of combination drug therapy schemes have been advocated as a high priority strategy if the control of this devastating disease is to be achieved. The groups of Prof Deborah Smith in the Centre for Immunology and Infection at the University of York and Dr. Silvia Uliana in the Biomedical Sciences Institute, University of Sao Paulo have been developing projects that aim to identify new alternatives for leishmaniasis treatment. Prof Smith leads a research consortium (including parasite and structural biologists, medicinal chemists and enzymologists, funded by the Wellcome Trust) that has identified myristoyl-CoA:protein N-myristoyltransferase (NMT) as a suitable candidate for drug development against some of the most devastating infections caused by protozoan parasites, including leishmaniasis. The research output to date has validated NMT as a target using both genetic and Chemical methods, leading to a recent high-throughput screen that identified small molecule inhibitors for the parasite NMTs. Focusing on VL and L. donovani, the consortium is now progressing to the validation of one or more clinical candidates for human trials. Dr. Uliana's group, funded by FAPESP, has described the antileishmanial activity of tamoxifen, a drug already in use for the treatment of breast câncer for over 30 years. Tamoxifen has been shown to be effective in several in vivo experimental models of visceral and cutaneous American leishmaniasis. The collaboration between Prof. Smith and Dr. Uliana's laboratory will open a new window of opportunity to strengthen the work in both research groups. The specific aims of this proposal are to test tamoxifen and other related SERMs in combination with small molecule NMT inhibitors in animal models of Old World visceral leishmaniasis and of American visceral and cutaneous leishmaniasis. It will also allow progress in the search for tamoxifen's mechanisms of action against the parasite and in the validation of this agent as a drug lead with the necessary broad activity desirable for a new anti-leishmanial drug. Joining efforts and combining the findings of the two ongoing projects may accelerate the identification of useful therapeutic combination schemes. (AU)