Antileishmanial Effects of Synthetic PIb Analogs Derived from the Entamoeba histolytica Lipopeptidephosphoglycan.

With an estimated number of new cases annually of approximately 1.4 million, leishmaniasis belongs to the most important parasitic diseases in the world. Nevertheless, existing drugs against leishmaniasis in general have several drawbacks that urgently necessitate new drug development. A glycolipid molecule of the intestinal protozoan parasite and its synthetic analogs previously showed considerable immunotherapeutic effects against infection. Here, we designed and synthesized a series of new immunostimulatory compounds derived from the phosphatidylinositol b anchor of (PIb) subunit of the native compound and investigated their antileishmanial activity and in a murine model of cutaneous leishmaniasis. The new synthetic PIb analogs showed almost no toxicity Treatment with the analogs significantly decreased the parasite load in murine and human macrophages In addition, topical application of the PIb analog Eh-1 significantly reduced cutaneous lesions in the murine model, correlating with an increase in the production of selected Th1 cytokines. In addition, we could show in experiments that treatment with Eh-1 led to a decrease in mRNA expression of arginase-1 (Arg1) and interleukin 4 (IL-4), which are required by the parasites to circumvent their elimination by the immune response. The use of the host-targeting synthetic PIb compounds, either alone or in combination therapy with antiparasitic drugs, shows promise for treating cutaneous leishmaniasis and therefore might improve the current unsatisfactory status of chemotherapy against this infectious disease.