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A selective inhibitor of the kinetoplastid proteasome (GNF6702) is identified that is highly efficacious in vivo , clearing the parasites that cause leishmaniasis, Chagas disease and sleeping sickness from mice, highlighting the possibility of developing a single class of drugs for these neglected diseases. Three tropical diseases targeted by new drug Chagas disease, leishmaniasis, and sleeping sickness are caused by the kinetoplastid parasites Trypanosoma cruzi , Leishmania spp. and Trypanosoma brucei spp., respectively, and affect 20 million people worldwide. This study reports the results of a screen to find new conserved molecular targets and broad spectrum drugs that could be used to treat all three diseases. A selective inhibitor of the kinetoplastid proteasome (GNF6702) was identified as the most effective. It is highly efficacious in vivo , clearing parasites from mice in all three models of infection. GNF6702 is a non-competitive inhibitor, specific for kinetoplastid proteasome, and is well-tolerated in mice. These results highlight the possibility of developing a single class of drugs for these neglected diseases. Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually 1 . The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi , Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target 2 . However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of [almost equal to]1.7 million compounds, we identified a diverse collection of [almost equal to]6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 μM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax , and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi . We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria. The lipid kinase phosphatidylinositol-4-OH kinase (PI(4)K) is identified as a target of the imidazopyrazines, a new antimalarial compound class that can inhibit several Plasmodium species at each stage of the parasite life cycle; the imidazopyrazines exert their inhibitory action by interacting with the ATP-binding pocket of PI(4)K. A multifunction target for antimalarials To eliminate malaria completely it is necessary to cure an individual of all stages in the malaria parasite's life cycle including the symptomatic blood-stage infection and the preceding liver-stage infection (to prevent relapse) and also to block transmission to mosquitoes. Here Elizabeth Winzeler and colleagues identify phosphatidylinositol-4-OH kinase (PI(4)K) as a potential drug target that is essential to fatty acid metabolism in all stages of the Plasmodium parasite. The authors show that a family of compounds with an imidazopyrazine core, distinct from known antimalarials, inhibits PI(4)K and also inhibits the development of multiple Plasmodium species at each stage of the life cycle. Their analyses reveal that the imidazopyrazines interact with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4 phosphate and interfering with cell division.

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of > 4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.

The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na + regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na + homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na + homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. Novel antimalarial drugs are urgently needed to combat parasite drug resistance. Here, Vaidya et al . describe a new chemical class of potent antimalarial compounds that act by disrupting the parasite's sodium homeostasis.

Calcium-dependent protein kinases play a crucial role in intracellular calcium signaling in plants, some algae and protozoa. In Plasmodium falciparum , calcium-dependent protein kinase 1 (PfCDPK1) is expressed during schizogony in the erythrocytic stage as well as in the sporozoite stage. It is coexpressed with genes that encode the parasite motor complex, a cellular component required for parasite invasion of host cells, parasite motility and potentially cytokinesis. A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability. An in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines. Compound treatment caused sudden developmental arrest at the late schizont stage in P. falciparum and a large reduction in intracellular parasites in Toxoplasma gondii , which suggests a possible role for PfCDPK1 in regulation of parasite motility during egress and invasion.

A selective inhibitor of the kinetoplastid proteasome (GNF6702) is identified that is highly efficacious in vivo, clearing the parasites that cause leishmaniasis, Chagas disease and sleeping sickness from mice, highlighting the possibility of developing a single class of drugs for these neglected diseases.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here, we identify a lipid kinase, phosphatidylinositol 4-kinase (PI4K), as the target of imidazopyrazines, a novel antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens, P. falciparum and P. vivax, and inhibit liver stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI4K, altering the intracellular distribution of phosphatidylinositol 4-phosphate. Collectively, our data define PI4K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

This dissertation is divided into five sections. The main focus of this dissertation is on development of new methods for transforming amino alcohols into various synthons. The major part of the work is devoted to Rh(II) catalyzed C-H insertion reactions and their application towards the formation of γ-lactams and isoquinolones. The introductory chapter sheds light on conversion of amino alcohols into various heterocycles. This section further focuses on various methods to form g-lactams and isoquinolones and the advantages and disadvantages with the existing methods. The second chapter of the thesis discusses the development of β-aminobromides. A mild and efficient method is developed for bromination of amino alcohols leading to the formation of rearranged amino bromides. These bromides are converted to original form without any stereochemical leakage upon treatment with oxygen and nitrogen nucleophiles. The reaction mechanism leading to the rearrangement and the effect of neighboring group is discussed in detail. The third chapter is devoted to selective protection of amino group of an amino alcohol as a dithiocarbamate. Despite plethora reactions involving amino alcohols, a very fundamental reaction involving selective protection of amino group is largely ignored. A chemoselective protocol involving an amino alcohol, carbon disulfide, and an alkyl halide in presence of cesium carbonate and TBAI leading to the formation of dithiocarbamate is developed. The reaction is short, simple and devoid of any side products. The fourth chapter deals with regioselective and stereoselective formation of γ-lactams. This methodology is based on Rh(II) C-H insertion of α-diazo α-(phenysulfonyl) acetamide leading to the formation of desired products in favorable ratios. The stereoelectronic effects leading to the desired product are discussed. This methodology was then applied towards the synthesis of Rolipram and Baclofen. Final chapter deals with formal C-H insertion of chiral aryl glycine derived α-diazo α-(phenysulfonyl) acetamides to give rise to chiral isoquinolones as a diastereomer. The mechanism leading to the formation of product is discussed.