title: Match-making for posaconazole through systems thinking.
abstract: Currently available drugs for Chagas' disease are limited by toxicity and low efficacy in the chronic stage. Posaconazole, the most advanced new anti-chagasic drug candidate, did not fully confirm its initial potential in a Phase II clinical trial for chronic Chagas' disease. Given that posaconazole is highly active against Trypanosoma cruzi in vitro, and was very well tolerated in clinical trials, it should not be abandoned. Rather, a combination therapy may provide a highly promising outlook. Systems-scale approaches facilitate the hunt for a combination partner for posaconazole, which acts by blocking sterol biosynthesis. Mounting evidence suggests the functional interactions between sterols and sphingolipids in vivo. Here, we propose combining sterol and sphingolipid biosynthesis inhibitors to advance drug development in Chagas' disease.
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland; University of Basel, CH-4000 Basel, Switzerland.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Fügi
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland; University of Basel, CH-4000 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland; University of Basel, CH-4000 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Tanner
authors.affiliation: University of Fribourg, CH-1700 Fribourg, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schneiter
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland; University of Basel, CH-4000 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mäser
authors.affiliation: Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland; University of Basel, CH-4000 Basel, Switzerland. Electronic address: xueli.guan@unibas.ch.
authors.forename: Xue Li
authors.initials: XL
authors.lastname: Guan
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy*; D017322:Clinical Trials, Phase II as Topic; D004359:Drug Therapy, Combination; D006801:Humans; D049490:Systems Biology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014345:Trypanosoma / Q000187:drug effects
chemical_list: D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole
keywords: Chagas’ disease; combination therapy; sphingolipids; sterols; systems biology