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Taxonomic group: protista / Evosea (Phylum: Evosea)
Host organism: Homo sapiens
Organ / tissue: Life stage: trophozoite
Associated disease: intestinal infections due to Entamoeba [ICD11: 1A36.0

, ICD11: XN3S1

]; amoebic liver abscess [ICD11: 1A36.10

, ICD11: XN3S1

]; infection due to Entamoeba histolytica [ICD11: XN82F

]

NCBI PubMed ID: 32393489
Publication DOI: 10.1128/AAC.00161-20
Journal NLM ID: 0315061
Correspondence: lotter

bnitm.de
Institutions: Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany, Department of Chemistry, University of Hamburg, Hamburg, Germany, Leishmaniasis Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany

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 Entamoeba histolytica and its synthetic analogs previously showed considerable immunotherapeutic effects against Leishmania major infection. Here, we designed and synthesized a series of new immunostimulatory compounds derived from the phosphatidylinositol b anchor of Entamoeba histolytica (EhPIb) subunit of the native compound and investigated their antileishmanial activity in vitro and in vivo in a murine model of cutaneous leishmaniasis. The new synthetic EhPIb analogs showed almost no toxicity in vitro Treatment with the analogs significantly decreased the parasite load in murine and human macrophages in vitro In addition, topical application of the EhPIb 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 in vitro 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 EhPIb 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.

glycolipid, leishmania, Entamoeba histolytica, immunostimulation

Structure type: oligomer
Location inside paper: Fig. 1a, 1b, EhLPPG
Trivial name: LPPG
Compound class: lipopeptidophosphoglycan
Contained glycoepitopes: IEDB_115013,IEDB_120354,IEDB_123890,IEDB_130645,IEDB_130701,IEDB_131186,IEDB_134624,IEDB_135818,IEDB_136906,IEDB_137472,IEDB_141181,IEDB_141793,IEDB_141794,IEDB_141807,IEDB_142488,IEDB_144983,IEDB_144987,IEDB_144998,IEDB_145001,IEDB_146664,IEDB_150900,IEDB_151528,IEDB_151531,IEDB_152206,IEDB_153220,IEDB_158538,IEDB_190606,IEDB_2346541,IEDB_742246,IEDB_918313,IEDB_983930,IEDB_983931,SB_163,SB_192,SB_198,SB_31,SB_44,SB_67,SB_7,SB_72,SB_87

Methods: chemical synthesis, cytotoxicity assay
Biological activity: In vitro activities of synthetic EhPIb analogs against L. major infection.
Comments, role: LIP = C30:1 = SMILES CCCCCCCC/C=C/CCCCCCCCCCCCCCCCCCCC(O)=O

NCBI Taxonomy refs (TaxIDs): 5759
Show glycosyltransferases

There are 32 chemically distinct structures. Please, select:

CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)COP(=O)(O)O[C@@H]1[C@@H](O[C@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]4O[C@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O[C@H]4O[C@H](COP(=O)(O)OCCN[1*]OC(=O)C(N)COP(=O)(O)O[C@H]5O[C@H](CO[C@@H]6O[C@H](CO[C@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@@H](O)[C@H](O)[C@H]6O)[C@H](O)[C@H](O)[C@H]5O)[C@H](O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@@H]3O)[C@H](O)[C@H]2N)[C@H](O)[C@@H](O)[C@H](O)[C@@H]1OC(=O)CCCCCCCCCCCCCCC

SVG MW SMILES 3D mol Ionize

R1 = polypeptide
Warning = sub-repeat ending at aDGalp: variable unit count (1-20) was assumed to be 1
Warning = sub-repeat ending at aDGlcp: variable unit count (1-22) was assumed to be 1