SBIR-STTR Award

This Phase I project pertains to the synthesis and biological evaluation of novel L-nucleoside-derived antimalarial compounds. A major recent finding has been that during the development of the malaria parasite in the host erythrocyte, profound alterations are caused in the permeability of the host cell-membrane. Recent investigations have discovered that a new transport pathway for nucleosides is induced by the parasite in the host cell membrane. This system is significantly different to any transport system in the host, and has opened the way for the design of selective new antimalarial drugs which cannot enter the host cell membrane (such as L-nucleoside conjugates with cytotoxic drugs). These compounds have the propensity to be toxic to the parasite without affecting the host cell. The development of this new approach to malaria chemotherapy is of major significance, as these compounds act by different mechanisms of action from conventional quinoline or acridine antimalarial drugs, and therefore should show no cross-resistance. At least thirty test compounds based on this concept will be synthesized and evaluated in Phase I studies. Compounds will be screened for activity against Plasmodium falciparum and their transport and mechanisms of action will be studied. Test compounds will also be submitted to the U.S. Army's antimalarial testing program. The project will likely produce a new class of antimalarial drugs for treatment of multi-drug resistant malaria. The disease kills over 2 million persons worldwide annually and affects over 300 million. There is therefore a considerable humanitarian benefit as well as commercial potential upon successful completion of the project goals.

Keywords:
Antimalarials Drug Resistance Purines Cytotoxic Pyrimidines Plasmodium L-Nucleosides

Based on the preliminary encouraging results obtained in Phase I feasibility study, it is proposed to design, synthesize and evaluate in biological antimalarial assays approximately forty new L-nucleoside conjugates and other dinucleoside phosate analogs. the synthesized chemicals will undergo an in-depth quantitative structure-activity relationship analysis. a major effort in the Phase II program will be dedicated to the synthesis of a radiolabeled dinucleoside phosphate. This material will enable a quantitative investigation of the transport mechanism, and uptake by both parasite invaded cells and normal red blood erythrocytes. Moreover, this material will be instrumental in determination of the drug metabolism and therefore will provide clarification on the mechanism of action of the drug. the best compounds, which will have submicromolar activity and minimal or no detectable toxicity will be scaled up for in vivo evaluation. Test compounds will also be submitted to the U.S. Army Antimalaria Test Program. Successful accomplishment of the proposed Phase II program will result in selection of one or two drug candidates for development in human clinical trials.

Benefits:
The project will likely produce a new class of antimalarial drugs for treatment of multi-drug resistant malaria. the disease kill over 2 million persons worldwide annually and affects 300 millions. There is therefore a considerable humanitarian benefit as well as commercial potential upon successful completion of the project goals.

Keywords:
Antimalarials Purines Pyrimidines Cytotoxic Plasmodium