X-ray Crystallography Contributions to Drug Discovery Against Parasite

doi:10.1016/bs.armc.2018.08.005

Annual Reports in Medicinal Chemistry

Volume 51, 2018, Pages 175-230

https://doi.org/10.1016/bs.armc.2018.08.005 Get rights and content

Abstract

Neglected tropical diseases, including malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis, are endemic in tropical/subtropical countries and affect over 1 billion people worldwide. X-ray crystallography is crucial for drug discovery platforms, providing essential insights into the mechanism of action and inhibition of protein targets to conceive potent and selective inhibitors. To date, hundreds of parasite proteins have been identified as validated or potential targets for the development of new drugs toward neglected tropical diseases. This review focuses on the structure and the inhibition of two enzyme targets, pteridine reductase and heat shock proteins, belonging to key metabolic pathways in protozoan parasites. We summarize here the large amount of structural information that has been reported on these enzymes, providing a key contribution to the rational design of potent inhibitors. The structure-based drug discovery approach has been proven to be a powerful strategy for the identification of new treatments for neglected tropical diseases.

Introduction

According to the World Health Organization, neglected tropical diseases affect over 1 billion people in tropical/subtropical countries (http://www.who.int/neglected_diseases/diseases/en/). Plasmodium and Trypanosoma parasites are etiological agents of neglected tropical diseases like malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis (human sleeping sickness) that are endemic in a large number of countries and threaten millions of people worldwide. Due to climate changes the incidence of such parasitic diseases is expected to expand in the next years, exacerbating public health issues, together with the related economic burden.¹ The currently available therapies against parasite diseases are characterized by poor efficacy, toxicity, and rapid insurgence of resistance,² and hence there is urgent need for new, improved drugs against neglected tropical diseases. Several private and public initiatives have been undertaken to promote research to fight these diseases; among these the Drugs for Neglected Diseases initiative (DNDi; http://www.dndi.org/about-dndi/), the Gates Foundation (https://www.gatesfoundation.org/What-We-Do/Global-Health/Neglected-Tropical-Diseases), and the EU funded 2013–17 FP7 projects such as ParaDDisE, KINDReD, PDE4NPD, and NMTrypI, joined in a Synergy program (http://fp7-nmtrypi.eu/projects.html). X-ray crystallography is a key component of a drug discovery platform as it provides essential clues about the mechanism of action and inhibition of protein targets, precious to conceive powerful inhibitors that may evolve into new drugs. Our laboratory participated to the NMTrypI project providing more than 60 X-ray crystal structures to the consortium and helping to develop new molecules active against parasites. To date, the TDR Targets Database (http://tdrtargets.org/) lists 319 proteins/enzymes, either validated or potential targets, from Leishmania and Trypanosoma species with released crystal structures in the Protein Data Bank (PDB). Reviewing all of them will require a much larger space than a single book chapter. We then decided to limit our contribution to review the recent crystallographic literature about two selected parasite proteins that have been and are subject of our studies. We will describe the structure and the inhibition of the validated targets pteridine reductase enzymes (PTRs), belonging to the folate pathway, and the heat shock proteins (Hsps) that are gaining interest as targets for parasitic diseases in the drug discovery community.

Section snippets

Pteridine Reductase From Protozoan Parasites

Protozoan parasites Trypanosoma and Leishmania are auxotrophic for folate and other pterins that are required in critical cellular metabolic pathways such as the biosynthesis of nucleic acids and proteins. Following uptake, pterins (such as biopterin or folate) undergo two successive reductions to yield the active tetrahydro forms.3, 4, 5 In trypanosomatids, two enzymes contribute to the provision of these reduced molecular species: the bifunctional enzyme dihydrofolate reductase-thymidylate

Hsp90 in Protozoan Parasites

Hsps (also known as stress proteins) are molecular chaperones that stabilize a wide variety of proteins in a folded and functional state.³⁷ These proteins are involved in key cellular pathways, including signal transduction, protein degradation, and stress resistance. Hsps are classified according to their molecular weight in five main classes: Hsp40, Hsp60, Hsp70, Hsp90 (including Hsp82–90), and Hsp100. A sixth class of proteins has been added to this classification, namely, the

Conclusions

Despite the huge amount of structural information reported on parasite PTR and Hsp90 enzymes, to date none of the molecules developed toward these targets has reached the clinical trials for the treatment of parasite diseases. Nonetheless, these structural studies have provided key information for the development of molecules targeting these enzymes. The rational design of new compounds, driven by the structural information achieved, has led to drastic improvements in the inhibitor potency and,

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Chapter Five - X-ray Crystallography Contributions to Drug Discovery Against Parasite

Abstract

Introduction

Section snippets

Pteridine Reductase From Protozoan Parasites

Hsp90 in Protozoan Parasites

Conclusions

J. Biol. Chem.

Exp. Parasitol.

J. Struct. Biol.

Structure

J. Biol. Chem.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

J. Mol. Biol.

Anal. Biochem.

Biochem. Pharmacol.

Bioorg. Med. Chem.

Biomed. J.

FEBS Open Bio

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Curr. Opin. Pharmacol.

Trans. R. Soc. Trop. Med. Hyg.

Infect. Dis.

Br. Med. Bull.

Proc. Natl. Acad. Sci. U. S. A.

Parasitology

EMBO J.

J. Med. Chem.

Nat. Struct. Biol.

Acta Crystallogr. D Biol. Crystallogr.

Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun.

Mol. Microbiol.

J. Med. Chem.

Curr. Pharm. Des.

Proc. Natl. Acad. Sci. U. S. A.

Acta Crystallogr. D Biol. Crystallogr.