general	prion	malaria
data mining	evolution	genomics	structure

MALARIA/PROTOZOA

Malaria was once thought to be under control and on the way to eradication, however, the parasites that cause malaria (Plasmodium ovale, P. malariae, P. vivax, and P. falciparum) have started developing drug resistance to current anti-malarial drugs such as chloroquinine. The death toll caused or contributed by the disease per year is greater than all of the deaths attributed to AIDS in the last 15 years. The costs of controlling and treating malarial parasites is a major burden to countries that can least afford it, but due to the ease of worldwide travel, malaria can easily spread to countries considered low risk.

Our goal is to find new drugs and drug targets against malaria and other parasitic diseases such as Chaga's disease. Our approach is to use rational drug design. Rational drug design is a process in which the structure of the target is used to guide routes of novel drug discovery. Structural information can be in the form of solved X-ray crystal diffraction patterns, NMR peak deconvolution, or homology-based models. However, obtaining good structural data is balanced by choosing the proper target. Target selection benefits from understanding the underlying biology of the target. Our lab has used the explosion of genomic and structural data in order to find novel drug-like compounds active against protozoan-caused diseases such as Chaga's disease (Trypanosome cruzi) and malaria (Plasmodium falciparum). In addition, we are using data generated by analysis of the P. falciparum genome to select new drug targets. Research in the lab occurs at all positions in the drug discovery pipeline including generation of homology models, docking small molecules to active sites, synthesis of compounds for structure-activity relationship studies, and compassionate care based drug treatment (link to prion page).

Current projects include targets such as cruzain (T. cruzi), falcipains (P. falciparum).

References:

Joachimiak M.P., Chang C., Rosenthal P.J., and Cohen, F.E. (2001) The impact of whole genome sequence data on drug discovery - a malaria case study. Molecular Medicine 10:698-710. PDF

Du, X., Guo, C., Hansell, E., Doyle, P.S., Caffrey, C.R., Holler, T.P., McKerrow, J.H., and Cohen, F.E. (2002) Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain. J. Med. Chem. 45:2695-2707. PDF