Plasmodium falciparum Apicoplast Drugs: Targets or Off-Targets? Cyrille Y. Bott e, Faustine Dubar, Geoffrey I. McFadden, Eric Mar echal,* and Christophe Biot* Laboratoire de Physiologie Cellulaire V eg etale, UMR 5168, CNRS, CEA, INRA, Universit e Joseph Fourier, Grenoble, France Plant Cell Biology Research Centre, School of Botany, University of Melbourne, Victoria 3010, Australia Unit e de Catalyse et Chimie du Solide, CNRS UMR 8181, Universit e Lille 1, Universit e Lille Nord de France, 59650 Villeneuve d’Ascq Cedex, France Unit e de Glycobiologie Structurale et Fonctionnelle, CNRS UMR 8576, IFR 147, Universit e Lille 1, Universit e Lille Nord de France, 59650 Villeneuve d'Ascq C edex, France

http://fad.macmate.me/McFadden_Lab/Mcfadden_Papers/2012/Botte_Chem_Revs_2012.pdf

Plasmodium falciparum Apicoplast Drugs: Targets or Off-Targets?

Malaria remains the world's most devastating tropical infectious disease with as many as 40% of the world population living in risk areas. The widespread resistance of Plasmodium parasites to the cost-effective chloroquine and antifolates has forced the introduction of more costly drug combinations, such as Coartem®. In the absence of a vaccine in the foreseeable future, one strategy to address the growing malaria problem is to identify and characterize new and durable antimalarial drug targets, the majority of which are parasite proteins. Biochemical and structure-activity analysis of these proteins is ultimately essential in the characterization of such targets but requires large amounts of functional protein. Even though heterologous protein production has now become a relatively routine endeavour for most proteins of diverse origins, the functional expression of soluble plasmodial proteins is highly problematic and slows the progress of antimalarial drug target discovery. Here the status quo of heterologous production of plasmodial proteins is presented, constraints are highlighted and alternative strategies and hosts for functional expression and annotation of plasmodial proteins are reviewed.

/pdf/heterologous-expression-of-plasmodial-proteins-for-3e9qi0tqaf.pdf

Heterologous expression of plasmodial proteins for structural studies and functional annotation

There continues to be a need for innovative and inexpensive drugs to treat diseases of the developing world.1,2 It is also important to link academic training and research to critical societal needs. Indiana University−Purdue University Indianapolis (IUPUI) is addressing both these concerns by developing a concept called “Distributed Drug Discovery” (D3).(3) This Perspective describes how D3 can harness combinatorial chemistry, distributed over multiple academic and industrial locations, to educate students while they perform a key role in the early stages of drug lead discovery for developing world and otherwise neglected diseases. Two other articles in this issue of the Journal of Combinatorial Chemistry present case histories implementing the chemistry component of D3. One involves replicated D3 syntheses in the United States, Poland, Russia, and Spain.(4) The second is an application in which students at IUPUI make analogs of a potential anticancer agent.(5) In this Perspective, D3 is discussed in three parts: (I) The Concept of D3, (II) The Role of Combinatorial Chemistry in D3, and (III) Implementation of D3.

https://pubs.acs.org/doi/pdf/10.1021/cc800183m

Distributed Drug Discovery, Part 1: Linking Academia and Combinatorial Chemistry to Find Drug Leads for Developing World Diseases

Malaria is still one of the most devastating infectious diseases, affecting hundreds of millions of patients worldwide. Even though there are several established drugs in clinical use for malaria treatment, there is an urgent need for new drugs acting through novel mechanisms of action due to the rapid development of resistance. Resistance emerges when the parasite manages to mutate the sequence of the drug targets to the extent that the protein can still perform its function in the parasite but can no longer be inhibited by the drug, which then becomes almost ineffective. The design of a new generation of malaria drugs targeting multiple essential proteins would make it more difficult for the parasite to develop full resistance without lethally disrupting some of its vital functions. The challenge is then to identify which set of Plasmodium falciparum proteins, among the millions of possible combinations, can be targeted at the same time by a given chemotype. To do that, we predicted first the targets of the close to 20,000 antimalarial hits identified recently in three independent phenotypic screening campaigns. All targets predicted were then projected onto the genome of P. falciparum using orthologous relationships. A total of 226 P. falciparum proteins were predicted to be hit by at least one compound, of which 39 were found to be significantly enriched by the presence and degree of affinity of phenotypically active compounds. The analysis of the chemically compatible target combinations containing at least one of those 39 targets led to the identification of a priority set of 64 multi-target profiles that can set the ground for a new generation of more robust malaria drugs.

/pdf/prediction-of-the-p-falciparum-target-space-relevant-to-59osbtkl49.pdf

Prediction of the P. falciparum target space relevant to malaria drug discovery.

https://repository.up.ac.za/bitstream/handle/2263/10210/Birkholtz_Exploring%282008%29.pdf?sequence=1

Exploring functional genomics for drug target and therapeutics discovery in Plasmodia

The organization and mining of malaria genomic and post-genomic data is highly motivated by the necessity to predict and characterize new biological targets and new drugs. Biological targets are sought in a biological space designed from the genomic data from Plasmodium falciparum, but using also the millions of genomic data from other species. Drug candidates are sought in a chemical space containing the millions of small molecules stored in public and private chemolibraries. Data management should therefore be as reliable and versatile as possible. In this context, we examined five aspects of the organization and mining of malaria genomic and post-genomic data: 1) the comparison of protein sequences including compositionally atypical malaria sequences, 2) the high throughput reconstruction of molecular phylogenies, 3) the representation of biological processes particularly metabolic pathways, 4) the versatile methods to integrate genomic data, biological representations and functional profiling obtained from X-omic experiments after drug treatments and 5) the determination and prediction of protein structures and their molecular docking with drug candidate structures. Progresses toward a grid-enabled chemogenomic knowledge space are discussed.

/pdf/integration-and-mining-of-malaria-molecular-functional-and-35ln3p2xgf.pdf

Integration and mining of malaria molecular, functional and pharmacological data: how far are we from a chemogenomic knowledge space?

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Integration and mining of malaria molecular, functional and pharmacological data: how far are we from a chemogenomic knowledge space?