farnesyl-pyrophosphate and Chagas-Disease

Drug repositioning aims to identify novel indications for existing drugs. One approach to repositioning exploits shared binding sites between the drug targets and other proteins. Here, we review the principle and algorithms of such target hopping and illustrate them in Chagas disease, an in Latin America widely spread, but neglected disease.. We demonstrate how target hopping recovers known treatments for Chagas disease and predicts novel drugs, such as the antiviral foscarnet, which we predict to target Farnesyl Pyrophosphate Synthase in Trypanosoma cruzi, the causative agent of Chagas disease.

Topics: Algorithms; Chagas Disease; Drug Repositioning; Humans; Models, Molecular; Polyisoprenyl Phosphates; Sesquiterpenes; Trypanocidal Agents; Trypanosoma cruzi

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

Topics: Animals; Chagas Disease; Chlorocebus aethiops; Crystallography, X-Ray; Diphosphonates; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Humans; Models, Molecular; Molecular Targeted Therapy; Polyisoprenyl Phosphates; Protein Binding; Quinuclidines; Sesquiterpenes; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells