Three-dimensional structures in the design of therapeutics targeting parasitic protozoa: reflections on the past, present and future

Abstract

Parasitic protozoa cause a range of diseases which threaten billions of human beings. They are responsible for tremendous mortality and morbidity in the least-developed areas of the world. Presented here is an overview of the evolution over the last three to four decades of structure-guided design of inhibitors, leads and drug candidates aiming at targets from parasitic protozoa. Target selection is a crucial and multi-faceted aspect of structure-guided drug design. The major impact of advances in molecular biology, genome sequencing and high-throughput screening is touched upon. The most advanced crystallographic techniques, including XFEL, have already been applied to structure determinations of drug targets from parasitic protozoa. Even cryo-electron microscopy is contributing to our understanding of the mode of binding of inhibitors to parasite ribosomes. A number of projects have been selected to illustrate how structural information has assisted in arriving at promising compounds that are currently being evaluated by pharmacological, pharmacodynamic and safety tests to assess their suitability as pharmaceutical agents. Structure-guided approaches are also applied to incorporate properties into compounds such that they are less likely to become the victim of resistance mechanisms. A great increase in the number of novel antiparasitic compounds will be needed in the future. These should then be combined into various multi-compound therapeutics to circumvent the diverse resistance mechanisms that render single-compound, or even multi-compound, drugs ineffective. The future should also see (i) an increase in the number of projects with a tight integration of structural biology, medicinal chemistry, parasitology and pharmaceutical sciences; (ii) the education of more `medicinal structural biologists' who are familiar with the properties that compounds need to have for a high probability of success in the later steps of the drug-development process; and (iii) the expansion of drug-development capabilities in middle- and low-income countries.

The calcium-dependent protein kinase 1 from Toxoplasma gondii as target for structure-based drug design

“…Therefore, new drug targets and novel therapies are urgently needed. In addition to high-throughput screening approaches (Norcliffe et al 2014 ), structure-based methods in close combination with medicinal chemistry and biophysical and biological validation have become powerful tools in the search of new drugs and treatments (Hunter, 2009 ; Verlinde et al 2009 ; Groftehauge et al 2015 ; Hol, 2015 ; Muller, 2017 ).…”

New developments in crystallography: exploring its technology, methods and scope in the molecular biosciences

“…All research results are published with no restriction [ 67 ]. There are also long traditions in the biological crystallography field of the studies of viruses on the one hand [ 68 , 69 ] and tropical diseases on the other [ 70 ]. A highly notable project is the structural genomics study of the MTb genome and its protein crystal structures ( http://webtb.org/ ).…”

Analysis of Base Excision and Single-Strand Break Repair Activities in Trypanosomatid Extracts

“…Examples of such novelties included mechanisms for expression of the large number of genes for variable surface glycoproteins (VSGs) responsible for antigenic variation in T. brucei; the unique form of nuclear DNA modification by base J; polycistronic transcripts and trans-splicing; glycophosphatidylinositol (GPI) anchors used for the attachment of proteins to the plasma membrane; the unique structure and peculiar replication processes of these parasites' mitochondrial genomes (or kinetoplast DNA); U-insertion/deletion editing of transcripts produced from mitochondrial gene expression; peroxisome-related organelles containing glycolytic enzymes called glycosomes; acidocalcisomes; a trypanothione-based system for combatting reactive oxygen species, and still others (for-in some cases personal-accounts of various of these discoveries, see [10][11][12][13]). Moreover, novel approaches and methods were applied in these early stages of trypanosomatid research that, at that time, were not yet standardly used elsewhere, such as structure-based drug design (reviewed in [14]) and metabolic control analysis of entire pathways using in silico models [15] and, at later stages, also in vivo systems [16].…”