This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The basis of the proposed work is to ask and answer questions in the arena of selective control of proteolytic action in parasitic disease. Our goal is to understand the function and regulation of proteolytic enzymes and to use structural biology to guide the design of potent, specific inhibitors. To achieve this, we use biochemical and structural biology technologies ? including high resolution x-ray crystallography. Targets under study include those pertinent to the goal of designing small molecule inhibitors to be optimized to new therapeutics for parasitic infection and are derived from the following organisms: cruzain and cruzipain 2, from Trypanosoma cruzi, TbCatB from Trypanosoma brucei rhodesiense, falcipain 3 from Plasmodium falciparum, EhCP4 from Entomeba histolytica and GlCP from Giardia lamblia. The diseases caused by these agents are, respectively, Chagas? disease, Human African Trypanosomiasis, malaria, amoebic colitis and giardiasis.