Malaria is considered today a major threat to the life of millions of human beings in various sections of the world. New chemotherapeutic strategies are in increasing demand as are basic studies which could provide the requisite scientific background for the development of those strategies. The present work is an attempt to study, at the molecular level, the role of the host cell membrane in the intraerythrocytic growth and propagation of the human malaria parasite P. falciparum, with particular emphasis on pores induced by the parasite in the host cell membrane. The ultimate goal is to provide a rational basis for the design of drugs or vaccines which will control parasite development at the various stages of the erythrocytic cycle. The project is based on the knowledge that alterations in the permselectivity properties of the host cell membrane appear at early stages of parasite growth, evolve in parallel to parasite growth, and are essential for parasite development. The proposed investigation will be carried out along two parallel routes aimed at: (a) Identification of the functional components of the pore, based on immunochemical and genetic tools, which encompass development of monoclonal antibodies (MABs) with pore-blocking capacity, and the use of mutants with modified pore activity. The identification is essential for the isolation, reconstitution and chemical characterization of the pores. The blocking MABs are essential not only for identification and assessment of the pores' functional role in intraerythrocytic parasite development but also for exploring their possible application as immunotherapeutic tools. (b) Development of chemical means to specifically arrest intraerythrocytic parasite growth, based on the design of antimalarial agents which are admitted preferentially or exclusively by the pores induced by the parasite. The present proposal constitutes a previously unexplored approach for the chemotherapeutic and immunological control of asexual malarial parasites, involving an interdisciplinary effort by an established laboratory in membrane transport and properties of malaria.
| Loyevsky, M; Cabantchik, Z I (1994) Antimalarial action of hydrophilic drugs: involvement of aqueous access routes to intracellular parasites. Mol Pharmacol 45:446-52 |
