Giardiasis is the most prevalent parasitic disease in the United States an ranks as a leading cause of diarrheal illness worldwide. Available drugs for the treatment of giardiasis have undesirable side-effects and may be carcinogenic. We have found that the method by which Giardia degrade the ubiquitous necleoside 5'- methylthioadenosine (MTA) differs from MTA catabolism in human cells. To exploit this difference, we synthesized analogs of methylthioribose (MTR), and MTA catabolite. Ithylthioribose (ETR), the ethyl analog of MTR, is active against Giardia species in vitro and in vivo and has no demonstrable effects on cultured human cells or intact miceThe ultimate purpose of the proposed research is to develop a new class of safe and effective agents for the treatment of giardiasis. The specific aims of Phase I of the project are 1) to determine the efficacy of ETR in vitro against several strains of G. lamblia including an analysis of cytocidal activity, 2) to determine the efficacy of ETR against G. lamblia (in adult mice) and G. lamblia (in neonatal mice) in two animal models of giardiasis, 3) to elucidate the mechanism of action of ETR, and 4) to synthesize and test additional MTR analogs against Giardia. The long term objectives and Phase II goals are to perform detailed toxicological and pharmacological analyses in preparation for future clinical trials.National Institute of Allergy and Infectious Diseases (NIAID)
