Targeting pathogen metabolism without collateral damage to the host

Jurgen R Haanstra,Amalia M Dolga,Hans V Westerhoff,Balázs Szöör,François Du Toit,Albert Gerding,Manon Buist-Homan,Freek J H Sorgdrager,Barbara M Bakker,Hermann-Georg Holzhütter,Keith R Matthews,Jacky L Snoep,Klaas Nico Faber

doi:10.1038/srep40406

Abstract

The development of drugs that can inactivate disease-causing cells (e.g. cancer cells or parasites) without causing collateral damage to healthy or to host cells is complicated by the fact that many proteins are very similar between organisms. Nevertheless, due to subtle, quantitative differences between the biochemical reaction networks of target cell and host, a drug can limit the flux of the same essential process in one organism more than in another. We identified precise criteria for this ‘network-based’ drug selectivity, which can serve as an alternative or additive to structural differences. We combined computational and experimental approaches to compare energy metabolism in the causative agent of sleeping sickness, Trypanosoma brucei, with that of human erythrocytes, and identified glucose transport and glyceraldehyde-3-phosphate dehydrogenase as the most selective antiparasitic targets. Computational predictions were validated experimentally in a novel parasite-erythrocytes co-culture system. Glucose-transport inhibitors killed trypanosomes without killing erythrocytes, neurons or liver cells.

Highlights

In the treatment of both cancer and infectious diseases, the major challenge is to design selective drugs that target the cancer cell or pathogen without harming the patient
The direct effect of the inhibitor on enzyme activity depends on concentrations of intracellular metabolites that act on the target enzyme
We developed the concept of network-based drug selectivity and applied it to glycolysis in Trypanosoma brucei – the parasite that causes African sleeping sickness – and glycolysis in the erythrocytes of its human host

Summary

Introduction

In the treatment of both cancer and infectious diseases, the major challenge is to design selective drugs that target the cancer cell or pathogen without harming the patient. Some very important enzymes are present in excess and need to be inhibited almost completely before cell function is affected, while others are present in limiting amounts[9] These two factors – interacting metabolite concentrations and the target enzyme’s degree of control over cell function – depend on the kinetic properties of the metabolic network as a whole and are important for the efficacy and selectivity of drugs in vivo. These network properties should be included when ranking putative drug targets. These aspects make erythrocytes well-suited for testing the validity of the concept of network-based drug target identification

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