Bioactivity of Farnesyltransferase Inhibitors Against Entamoeba histolytica and Schistosoma mansoni

Abstract

The protozoan parasite Entamoeba histolytica can induce amebic colitis and amebic liver abscess. First-line drugs for the treatment of amebiasis are nitroimidazoles, particularly metronidazole. Metronidazole has side effects and potential drug resistance is a concern. Schistosomiasis, a chronic and painful infection, is caused by various species of the Schistosoma flatworm. There is only one partially effective drug, praziquantel, a worrisome situation should drug resistance emerge. As many essential metabolic pathways and enzymes are shared between eukaryotic organisms, it is possible to conceive of small molecule interventions that target more than one organism or target, particularly when chemical matter is already available. Farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway, is vital for diverse functions, including cell differentiation and growth. Both E. histolytica and Schistosoma mansoni genomes encode FT genes. In this study, we phenotypically screened E. histolytica and S. mansoni in vitro with the established FT inhibitors, lonafarnib and tipifarnib, and with 125 tipifarnib analogs previously screened against both the whole organism and/or the FT of Trypanosoma brucei and Trypanosoma cruzi . For E. histolytica , we also explored whether synergy arises by combining lonafarnib and metronidazole or lonafarnib with statins that modulate protein prenylation. We demonstrate the anti-amebic and anti-schistosomal activities of lonafarnib and tipifarnib, and identify 17 tipifarnib analogs with more than 75% growth inhibition at 50 μM against E. histolytica . Apart from five analogs of tipifarnib exhibiting activity against both E. histolytica and S. mansoni , 10 additional analogs demonstrated anti-schistosomal activity (severe degenerative changes at 10 μM after 24 h). Analysis of the structure-activity relationship available for the T. brucei FT suggests that FT may not be the relevant target in E. histolytica and S. mansoni . For E. histolytica , combination of metronidazole and lonafarnib resulted in synergism for growth inhibition. Also, of a number of statins tested, simvastatin exhibited moderate anti-amebic activity which, when combined with lonafarnib, resulted in slight synergism. Even in the absence of a definitive molecular target, identification of potent anti-parasitic tipifarnib analogs encourages further exploration while the synergistic combination of metronidazole and lonafarnib offers a promising treatment strategy for amebiasis.

Recent Advances in Anti-Schistosomiasis Drug Discovery

“…Other S. mansoni targets being investigated for new antischistosomal drugs include phosphodiesterase-4 [140][141][142], dihydroorotate dehydrogenase [143], 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [144,145], farnesyl transferase [146], carbonic anhydrase [147], NAD+ catabolizing enzyme [148], cytochrome P450 (CYP3050A1) [149] and aldose reductase [9,150,151…”

In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against Naegleria fowleri

“…Protein farnesyltransferase (FT) uses farnesyl pyrophosphate to attach farnesyl group to specific proteins and this prenylation is an important process to mediate protein-protein interactions and protein-membrane interactions [ 17 ]. Since the genome of N. fowleri contains a gene encoding FT (Accession number NF0130130) and compounds targeting FT of other protozoan parasites led to severe impairment of growth of Trypanosoma cruzi , Leishmania major , Plasmodium falciparum and Entamoeba histolytica [ 18 , 19 , 20 , 21 ], we investigated the effect of a well-characterized, late-stage clinical FT inhibitor lonafarnib against multiple strains of N. fowleri . We also determined the effect of the combination of pitavastatin, an HMGR inhibitor, that targets the second step of the mevalonate pathway, and the FT inhibitor lonafarnib that acts at the end of the mevalonate pathway.…”

Joining forces: Leveraging novel combination therapies to combat infections with eukaryotic pathogens

“…Farnesyltransferase is an essential enzyme that catalyzes the posttranslational attachment of farnesyl groups on proteins. Combination therapy with simvastatin and lonafarnib, an antineoplastic that inhibits farnesyltransferase [ 29 ], was synergistic against Entamoeba histolytica [ 30 ]. This finding was unanticipated because genome data suggest that E .…”

“…Combination therapy with the standard antiprotozoal, metronidazole, and lonafarnib was also synergistic against E . histolytica [ 30 ]. This outcome may have been due to lonafarnib-induced membrane destabilization, caused by impaired protein prenylation, which, in turn, intensified oxidative damage caused by metronidazole.…”