Biological Studies and Target Engagement of the 2- C-Methyl-d-Erythritol 4-Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1 R,3 S)-MMV008138 and Analogs.

Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2- C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure-activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents.

[1]  N. Strynadka,et al.  Structural Insights into Inhibition of Escherichia coli Penicillin-binding Protein 1B* , 2016, The Journal of Biological Chemistry.

[2]  N. Strynadka,et al.  Escherichia coli Penicillin-Binding Protein 1B: Structural Insights into Inhibition. , 2016 .

[3]  Manuel Llinás,et al.  Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond , 2016, PLoS pathogens.

[4]  D. Vertommen,et al.  ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan , 2016, Nature Communications.

[5]  Jeremy L. Praissman,et al.  The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition , 2016, eLife.

[6]  T. Brummelkamp,et al.  Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation. , 2015, Chemistry & biology.

[7]  Christopher M. Armstrong,et al.  Plasmodium IspD (2-C-Methyl-D-erythritol 4-Phosphate Cytidyltransferase), an Essential and Druggable Antimalarial Target. , 2015, ACS infectious diseases.

[8]  M. Cassera,et al.  Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138, and initial structure-activity studies. , 2015, Bioorganic & medicinal chemistry letters.

[9]  M. Cassera,et al.  Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum , 2014, Eukaryotic Cell.

[10]  J. Derisi,et al.  A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis , 2014, Antimicrobial Agents and Chemotherapy.

[11]  M. Cassera,et al.  Comprehensive quantitative analysis of purines and pyrimidines in the human malaria parasite using ion-pairing ultra-performance liquid chromatography-mass spectrometry. , 2014, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[12]  Y. Li,et al.  Biomarkers identified by urinary metabonomics for noninvasive diagnosis of nutritional rickets. , 2014, Journal of proteome research.

[13]  F. Diederich,et al.  Pseudilins: halogenated, allosteric inhibitors of the non-mevalonate pathway enzyme IspD. , 2014, Angewandte Chemie.

[14]  M. Cassera,et al.  Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box , 2013, Antimicrobial Agents and Chemotherapy.

[15]  J. Bessoule,et al.  Host-Pathogen Interaction and Signaling Molecule Secretion Are Modified in the dpp3 Knockout Mutant of Candida lusitaniae , 2013, Infection and Immunity.

[16]  G. V. van Dooren,et al.  The algal past and parasite present of the apicoplast. , 2013, Annual review of microbiology.

[17]  Jeremy N. Burrows,et al.  The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases , 2013, PloS one.

[18]  Jordi Perez-Gil,et al.  Metabolic plasticity for isoprenoid biosynthesis in bacteria. , 2013, The Biochemical journal.

[19]  M. Scholfield,et al.  Halogen bonding (X‐bonding): A biological perspective , 2013, Protein science : a publication of the Protein Society.

[20]  G. McFadden,et al.  Targeting apicoplasts in malaria parasites , 2013, Expert opinion on therapeutic targets.

[21]  Christian Gilissen,et al.  Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan , 2012, Nature Genetics.

[22]  Francesco Muntoni,et al.  ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome , 2012, Nature Genetics.

[23]  Francisco-Javier Gamo,et al.  Global phenotypic screening for antimalarials. , 2012, Chemistry & biology.

[24]  Joseph L. DeRisi,et al.  Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage Plasmodium falciparum , 2011, PLoS biology.

[25]  G. McFadden,et al.  Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii , 2011, The Journal of experimental medicine.

[26]  P. Roepe,et al.  Plasmodium falciparum resistance to cytocidal versus cytostatic effects of chloroquine. , 2011, Molecular and biochemical parasitology.

[27]  K. M. Watts,et al.  A second target of the antimalarial and antibacterial agent fosmidomycin revealed by cellular metabolic profiling. , 2011, Biochemistry.

[28]  A. Magill,et al.  Doxycycline for Malaria Chemoprophylaxis and Treatment: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis , 2011, The American journal of tropical medicine and hygiene.

[29]  W. V. Van Voorhis,et al.  Functional genetic analysis of the Plasmodium falciparum deoxyxylulose 5-phosphate reductoisomerase gene. , 2010, Molecular and biochemical parasitology.

[30]  P. Rosenthal,et al.  Apicoplast translation, transcription and genome replication: targets for antimalarial antibiotics. , 2008, Trends in parasitology.

[31]  M. Cassera,et al.  Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum. , 2007, Memorias do Instituto Oswaldo Cruz.

[32]  Joseph L. DeRisi,et al.  Tetracyclines Specifically Target the Apicoplast of the Malaria Parasite Plasmodium falciparum , 2006, Antimicrobial Agents and Chemotherapy.

[33]  M. Pop,et al.  Metagenomic Analysis of the Human Distal Gut Microbiome , 2006, Science.

[34]  M. Cassera,et al.  The Methylerythritol Phosphate Pathway Is Functionally Active in All Intraerythrocytic Stages of Plasmodium falciparum* , 2004, Journal of Biological Chemistry.

[35]  Y. Horiguchi,et al.  A Synthesis of Chiral 1,1,3-Trisubstituted 1,2,3,4-Tetrahydro-β-carbolines by the Pictet—Spengler Reaction of Tryptophan and Ketones: Conversion of (1R,3S)-Diastereomers into Their (1S,3S)-Counterparts by Scission of the C(1)—N(2) Bond. , 2004 .

[36]  P. Wilairat,et al.  Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening , 2004, Antimicrobial Agents and Chemotherapy.

[37]  Y. Horiguchi,et al.  A synthesis of chiral 1,1,3-trisubstituted 1,2,3,4-tetrahydro-beta-carbolines by the Pictet-Spengler reaction of tryptophan and ketones: conversion of (1R,3S)-diastereomers into their (1S,3S)-counterparts by scission of the C(1)-N(2) bond. , 2003, Chemical & pharmaceutical bulletin.

[38]  H. Lichtenthaler,et al.  Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. , 1999, Science.

[39]  Robert W. Weber,et al.  General method for the assignment of stereochemistry of 1,3-disubstituted 1,2,3,4-tetrahydro-.beta.-carbolines by carbon-13 spectroscopy , 1980 .

[40]  C. Dolea,et al.  World Health Organization , 1949, International Organization.