SPHINGOLIPID SYNTHESIS AS A TARGET FOR CHEMOTHERAPY AGAINST MALARIA PARASITES

The human malaria parasite Plasmodium falciparum contains sphingomyeli n synthase in its Golgi apparatus and in a network of tubovesicular me mbranes in the cytoplasm of the infected erythrocyte. Palmitoyl and de canoyl analogues of 1-phenyl-2-acylamino 3-morpholino-1-propanol inhib it the enzyme activity in infected erythrocytes. An average of 35% of the activity is extremely sensitive to these drugs and undergoes a rap id, linear decrease at drug concentrations of 0.05-1 mu M. The remaini ng 65% suffers a slower linear inhibition at drug concentrations rangi ng from 25 to 500 mu M. Evidence is presented that inhibition of the s ensitive fraction alone selectively disrupts the appearance of the int erconnected tubular network in the host cell cytoplasm, without blocki ng secretory development at the parasite plasma membrane or in organel les within the parasite, such as the Golgi and the digestive food vacu ole, This inhibition also blocks parasite proliferation in culture, in dicating that the sensitive sphingomyelin synthase activity as well as the tubovesicular network may provide rational targets for drugs agai nst malaria.