Ether lipid (alkylphospholipid) analogs as antileishmanial drugs

The parasitic protozoal disease leishmaniasis causes high morbidity worldwi de as well as mortality in visceral manifestations. Treatment regimens have been mainly dependent on antimony compounds; however, all treatments avail able to date have serious side effects and increasing cases of resistance h ave been reported. Additionally, these drugs have to be given parenterally and most are very costly. Ether lipid analogs are a new class of compounds, which have been characterized intensively in respect to their anticancer a ctivity and more recently their antileishmanial activity. For the alkyllyso phospholipids edelfosine and ilmofosine, as well as the alkylphosphocholine miltefosine, a very good in vitro and in vivo antileishmanial activity has been shown. Other analogs of the latter compound proved to be similarly ac tive or even better in in vitro systems. The mode of action of the alkylpho sphocholines in cancer cells is not yet fully understood, although interfer ence with phosphoinositide metabolism is most likely to play an important r ole. In Leishmania, some similarities of the mode of action to cancer cells could be demonstrated. Phospholipid biosynthesis was inhibited by miltefos ine and edelfosine in cancer cells as well as in Leishmania. For the latter organisms alkylphospholipid acyltransferases were inhibited after incubati on with the two compounds. Preliminary data suggest that glycosomes with th eir acyltransferases are involved in this process. Other mechanisms seem to differ, for example, glycolipid synthesis which was stimulated in cancer c ells, is in fact inhibited in Leishmania. Signal transduction perturbation has been widely investigated in cancer cells, but studies in Leishmania hav e just begun, therefore, a direct comparison cannot be made at present. Dur ing the digenic life cycle of Leishmania the interaction of potential thera peutics with macrophages is of major importance since these cells host the parasites in mammals. An interaction of alkylphosphocholines with the immun e system has been described and a direct activity in Leishmania-infected ma crophages should be investigated. In conclusion, the antimetabolic action o f ether lipid analogs could result in perturbation of the biosynthesis of k ey leishmanial membrane glycolipids and glycoproteins. Therefore, ether lip id analogs such as the alkylphosphocholines hold considerable promise as ne w antileishmanial drugs. (C) 1998 Prous Science. All rights reserved.