Abstract
Chagas' disease, which is caused by the Trypanosoma cruzi parasite, has become a global health problem that is currently treated with poorly tolerated drugs that require prolonged dosing. Therefore, there is a clinical need for new therapeutic agents that can mitigate these issues. The phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GDP-MP) enzymes form part of the de novo biosynthetic pathway to the nucleotide sugar GDP-mannose. This nucleotide sugar is used either directly, or indirectly via the formation of dolichol-phosphomannose, for the assembly of all mannose-containing glycoconjugates. In T. cruzi, mannose-containing glycoconjugates include the cell-surface glycoinositol-phospholipids and the glycosylphosphatidylinositol-anchored mucin-like glycoproteins that dominate the cell surface architectures of all life cycle stages. This makes PMM and GDP-MP potentially attractive targets for a drug discovery program against Chagas' disease. To assess the ligandability of these enzymes in T. cruzi, we have screened 18,117 structurally diverse compounds exploring drug-like chemical space and 16,845 small polar fragment compounds using an assay interrogating the activities of both PMM and GDP-MP enzymes simultaneously. This resulted in 48 small fragment hits, and on retesting 20 were found to be active against the enzymes. Deconvolution revealed that these were all inhibitors of T. cruzi GDP-MP, with compounds 2 and 3 acting as uncompetitive and competitive inhibitors, respectively. Based on these findings, the T. cruzi PMM and GDP-MP enzymes were deemed not ligandable and poorly ligandable, respectively, using small molecules from conventional drug discovery chemical space. This presents a significant hurdle to exploiting these enzymes as therapeutic targets for Chagas' disease.
Highlights
Chagas’ disease, which is caused by the Trypanosoma cruzi parasite, has become a global health problem that is currently treated with poorly tolerated drugs that require prolonged dosing
T. cruzi is known to produce an array of mannose-containing glycoconjugates, such as glycoinositol phospholipids (GIPLs) and glycosylphosphatidylinositol (GPI)-anchored mucin-like glycoproteins, trans-sialidase enzymes, and other N-glycosylated glycoproteins, which coat the outer surface of the parasite [5,6,7,8]
Drug discovery efforts utilizing high-throughput screening [19] and target-based design [20] approaches have been able to identify a small number of inhibitors of the L. mexicana and L. donovani GDP-mannose pyrophosphorylase (GDP-MP) enzymes that were capable of killing the parasites in vitro
Summary
Chagas’ disease, which is caused by the Trypanosoma cruzi parasite, has become a global health problem that is currently treated with poorly tolerated drugs that require prolonged dosing. In T. cruzi, mannose-containing glycoconjugates include the cell-surface glycoinositol-phospholipids and the glycosylphosphatidylinositol-anchored mucin-like glycoproteins that dominate the cell surface architectures of all life cycle stages This makes PMM and GDP-MP potentially attractive targets for a drug discovery program against Chagas’ disease. The T. cruzi PMM and GDP-MP enzymes were deemed not ligandable and poorly ligandable, respectively, using small molecules from conventional drug discovery chemical space This presents a significant hurdle to exploiting these enzymes as therapeutic targets for Chagas’ disease. T. cruzi is known to produce an array of mannose-containing glycoconjugates, such as glycoinositol phospholipids (GIPLs) and glycosylphosphatidylinositol (GPI)-anchored mucin-like glycoproteins, trans-sialidase enzymes, and other N-glycosylated glycoproteins, which coat the outer surface of the parasite [5,6,7,8]. Drug discovery efforts utilizing high-throughput screening [19] and target-based design [20] approaches have been able to identify a small number of inhibitors of the L. mexicana and L. donovani GDP-MP enzymes that were capable of killing the parasites in vitro
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