Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening

References

• WHO. Research priorities for Chagas disease, Human African Trypanosomiasis and Leishmaniasis. Technical report of the TDR disease reference group on Chagas disease, Human African Trypanosomiasis and Leishmaniasis. Technical Report 2012. https://apps.who.int/iris/handle/10665/77472
   Google Scholar
• Comini MA, Flohé L. The trypanothione-based redox metabolism of trypanosomatids. In: T Jäger, O Koch, L Flohé, eds. Trypanosomatids diseases: molecular routes to drug discovery (drug discovery in infectious diseases). Oxford: Wiley-Blackwell; 2013:167–199.
   Google Scholar
• Anantharaman V, Aravind L. Evolutionary history, structural features and biochemical diversity of the NlpC/P60 superfamily of enzymes. Genome Biol 2003;4:R11.
   PubMed Web of Science ®Google Scholar
• Fawaz MV, Topper ME, Firestine SM. The ATP-grasp enzymes. Bioorg Chem 2011;39:185–91.
   PubMed Web of Science ®Google Scholar
• Comini MA, Biosynthesis of polyamine–glutathione derivatives in Enterobacteria and Kinetoplastida. In: L Flohé, ed. Glutathione. London: CRC Press; 2018:285–305.
   Google Scholar
• Comini MA, Guerrero SA, Haile S, et al. Validation of Trypanosoma brucei trypanothione synthetase as drug target. Free Radic Biol Med 2004;36:1289–302.
   PubMed Web of Science ®Google Scholar
• Ariyanayagam MR, Oza SL, Guther ML, Fairlamb AH. Phenotypic analysis of trypanothione synthetase knockdown in the African trypanosome. Biochem J 2005;391:425–32.
   PubMed Web of Science ®Google Scholar
• Sousa AF, Gomes-Alves AG, Benítez D, et al. Genetic and chemical analyses reveal that trypanothione synthetase but not glutathionylspermidine synthetase is essential for Leishmania infantum. Free Radic Biol Med 2014;73:229–38.
   PubMed Web of Science ®Google Scholar
• Mesías AC, Sasoni N, Arias DG, et al. Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi. Free Radic Biol Med 2019;130:23–34.
   PubMed Web of Science ®Google Scholar
• Manta B, Bonilla M, Fiestas L, et al. Polyamine-based thiols in trypanosomatids: evolution, protein structural adaptations, and biological functions. Antioxid Redox Signal 2018;28:463–86.
   PubMed Web of Science ®Google Scholar
• Wyllie S, Oza SL, Patterson S, et al. Dissecting the essentiality of the bifunctional trypanothione synthetase-amidase in Trypanosoma brucei using chemical and genetic methods. Mol Microbiol 2009;74:529–40.
   PubMed Web of Science ®Google Scholar
• Torrie LS, Wyllie S, Spinks D, et al. Chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis. J Biol Chem 2009;284:36137–45.
   PubMed Web of Science ®Google Scholar
• Medeiros A, Benítez D, Korn RS, et al. Mechanistic and biological characterisation of novel N5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania. J Enzyme Inhib Med Chem 2020;35:1345–58.
   PubMed Web of Science ®Google Scholar
• Olin-Sandoval V, González-Chávez Z, Berzunza-Cruz M, et al. Drug target validation of the trypanothione pathway enzymes through metabolic modelling. Febs J 2012;279:1811–33.
   PubMed Web of Science ®Google Scholar
• Chen S, Lin CH, Walsh CT, Coward JK. Novel inhibitors of trypanothione biosynthesis: synthesis and evaluation of a phosphinate analog of glutathionyl spermidine (GSP), a potent, slow binding inhibitor of GSP synthetase. Bioorg Med Chem Lett 1997;7:505–10.
   Web of Science ®Google Scholar
• Chen S, Lin CH, Kwon DS, et al. Design, synthesis, and biochemical evaluation of phosphonate and phosphonamidate analogs of glutathionylspermidine as inhibitors of glutathionylspermidine synthetase/amidase from Escherichia coli. J Med Chem 1997;40:3842–50.
   PubMed Web of Science ®Google Scholar
• Verbruggen C, De Craecker S, Rajan PK, et al. Phosphonic acid and phosphinic acid tripeptides as inhibitors of glutathionylspermidine synthetase. Bioorg Med Chem Lett 1996;6:253–8.
   Web of Science ®Google Scholar
• Kwon DS, Lin CH, Chen S, et al. Dissection of glutathionylspermidine synthetase/amidase from Escherichia coli into autonomously folding and functional synthetase and amidase domains. J Biol Chem 1997;272:2429–36.
   PubMed Web of Science ®Google Scholar
• Lin CH, Chen S, Kwon DS, et al. Aldehyde and phosphinate analogs of glutathione and glutathionylspermidine: potent, selective binding inhibitors of the E. coli bifunctional glutathionylspermidine synthetase/amidase. Chem Biol 1997;4:859–66.
   PubMedGoogle Scholar
• Amssoms K, Oza SL, Ravaschino E, et al. Glutathione-like tripeptides as inhibitors of glutathionylspermidine synthetase. Part 1: substitution of the glycine carboxylic acid group. Bioorg Med Chem Lett 2002;12:2553–6.
   PubMed Web of Science ®Google Scholar
• Amssoms K, Oza SL, Augustyns K, et al. Glutathione-like tripeptides as inhibitors of glutathionylspermidine synthetase. Part 2: substitution of the glycine part. Bioorg Med Chem Lett 2002;12:2703–5.
   PubMed Web of Science ®Google Scholar
• Oza SL, Chen S, Wyllie S, et al. ATP-dependent ligases in trypanothione biosynthesis-kinetics of catalysis and inhibition by phosphinic acid pseudopeptides. Febs J 2008;275:5408–21.
   PubMed Web of Science ®Google Scholar
• D'Silva C, Daunes S. Structure-activity study on the in vitro antiprotozoal activity of glutathione derivatives. J Med Chem 2000;43:2072–8.
   PubMed Web of Science ®Google Scholar
• Spinks D, Torrie LS, Thompson S, et al. Design, synthesis and biological evaluation of Trypanosoma brucei trypanothione synthetase inhibitors. ChemMedChem 2012;7:95–106.
   PubMed Web of Science ®Google Scholar
• Benítez D, Medeiros A, Fiestas L, et al. Identification of novel chemical scaffolds inhibiting trypanothione synthetase from pathogenic trypanosomatids. PLoS Negl Trop Dis 2016;10:e0004617.
   PubMed Web of Science ®Google Scholar
• Orban OC, Korn RS, Benítez D, et al. 5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms. Bioorg Med Chem 2016;24:3790–800.
   PubMed Web of Science ®Google Scholar
• Biebinger S, Wirtz LE, Lorenz P, Clayton C. Vectors for inducible expression of toxic gene products in bloodstream and procyclic Trypanosoma brucei. Mol Biochem Parasitol 1997;85:99–112.
   PubMed Web of Science ®Google Scholar
• Gutscher M, Pauleau AL, Marty L, et al. Real-time imaging of the intracellular glutathione redox potential. Nat Methods 2008;5:553–9.
   PubMed Web of Science ®Google Scholar
• Hirumi H, Hirumi K. Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. J Parasitol 1989;75:985–9.
   PubMed Web of Science ®Google Scholar
• Maiwald F, Benítez D, Charquero D, et al. 9- and 11-Substituted 4-azapaullones are potent and selective inhibitors of African trypanosoma. Eur J Med Chem 2014;83:274–83.
   PubMed Web of Science ®Google Scholar
• Carvalho PC, Lima DB, Leprevost FV, et al. Integrated analysis of shotgun proteomic data with PatternLab for proteomics 4.0. Nat Protoc 2016;11:102–17.
   PubMed Web of Science ®Google Scholar
• Perez-Riverol Y, Csordas A, Bai J, et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res 2019;47:D442–50.
   PubMed Web of Science ®Google Scholar
• Oza SL, Ariyanayagam MR, Aitcheson N, Fairlamb AH. Properties of trypanothione synthetase from Trypanosoma brucei. Mol Biochem Parasitol 2003;131:25–33.
   PubMed Web of Science ®Google Scholar
• Zhang JH, Chung TD, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 1999;4:67–73.
   PubMed Web of Science ®Google Scholar
• Don R, Ioset JR. Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections. Parasitology 2014;141:140–6.
   PubMed Web of Science ®Google Scholar
• Ebersoll S, Bogacz M, Günter LM, et al. A tryparedoxin-coupled biosensor reveals a mitochondrial trypanothione metabolism in trypanosomes. Elife 2020;9:e53227.
   PubMed Web of Science ®Google Scholar
• Franco J, Sardi F, Szilágyi L, et al. Diglycosyl diselenides alter redox homeostasis and glucose consumption of infective African trypanosomes. Int J Parasitol Drugs Drug Resist 2017;7:303–13.
   PubMed Web of Science ®Google Scholar
• Franco J, Medeiros A, Benítez D, et al. In vitro activity and mode of action of distamycin analogues against African trypanosomes. Eur J Med Chem 2017;126:776–88.
   PubMed Web of Science ®Google Scholar
• Rodríguez Arce E, Putzu E, Lapier M, et al. New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents. Dalton Trans 2019;48:7644–58.
   PubMed Web of Science ®Google Scholar
• Franco J, Scarone L, Comini MA. Novel distamycin analogues that block the cell cycle of African trypanosomes with high selectivity and potency. Eur J Med Chem 2020;189:112043.
   PubMed Web of Science ®Google Scholar
• Rivas F, Medeiros A, Quiroga C, et al. New Pd-Fe ferrocenyl antiparasitic compounds with bioactive 8-hydroxyquinoline ligands: a comparative study with their Pt-Fe analogues. Dalton Trans 2021;50:1651–65.
   PubMed Web of Science ®Google Scholar
• Ortíz C, Moraca F, Laverriere M, et al. Glucose 6-phosphate dehydrogenase from trypanosomes: selectivity for steroids and chemical validation in bloodstream Trypanosoma brucei. Molecules 2021;26:358.
   PubMed Web of Science ®Google Scholar
• Franco J, Scarone L, Comini MA, Drugs and drug resistance in African and American Trypanosomiasis. In: M Botta, ed. Annual reports in medicinal chemistry: neglected diseases: extensive space for modern drug discovery. New York (NY): Academic Press, Elsevier Inc.; 2018:97–133.
   Google Scholar
• Talevi A, Carrillo C, Comini M. The thiol-polyamine metabolism of Trypanosoma cruzi: molecular targets and drug repurposing strategies. Curr Med Chem 2019;26:6614–35.
   PubMed Web of Science ®Google Scholar
• Saccoliti F, Di Santo R, Costi R. Recent advancement in the search of innovative antiprotozoal agents targeting trypanothione metabolism. ChemMedChem 2020;15:2420–35.
   PubMed Web of Science ®Google Scholar
• Fyfe PK, Oza SL, Fairlamb AH, Hunter WN. Leishmania trypanothione synthetase-amidase structure reveals a basis for regulation of conflicting synthetic and hydrolytic activities. J Biol Chem 2008;283:17672–80.
   PubMed Web of Science ®Google Scholar
• Koch O, Cappel D, Nocker M, et al. Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase. PLoS One 2013;8:e56788.
   PubMed Web of Science ®Google Scholar
• Leroux AE, Haanstra JR, Bakker BM, Krauth-Siegel RL. Dissecting the catalytic mechanism of Trypanosoma brucei trypanothione synthetase by kinetic analysis and computational modeling. J Biol Chem 2013;288:23751–64.
   PubMed Web of Science ®Google Scholar
• Duty S, Jenner P. Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 2011;164:1357–91.
   PubMed Web of Science ®Google Scholar
• Simeonov A, Kulkarni A, Dorjsuren D, et al. Identification and characterization of inhibitors of human apurinic/apyrimidinic endonuclease APE1. PLoS One 2009;4:e57403rd.
   Web of Science ®Google Scholar
• Chandramouly G, McDevitt S, Sullivan K, et al. Small-molecule disruption of RAD52 rings as a mechanism for precision medicine in BRCA-deficient cancers. Chem Biol 2015;22:1491–504.
   PubMedGoogle Scholar
• Devkota AK, Tavares CD, Warthaka M, et al. Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact. Biochemistry 2012;51:2100–12.
   PubMed Web of Science ®Google Scholar
• Kim W, Fricke N, Conery AL, et al. NH125 kills methicillin-resistant Staphylococcus aureus persisters by lipid bilayer disruption. Future Med Chem 2016;8:257–69.
   PubMed Web of Science ®Google Scholar
• Vlachojannis C, Magora F, Chrubasik S. Rise and fall of oral health products with Canadian bloodroot extract. Phytother Res 2012;26:1423–6.
   PubMed Web of Science ®Google Scholar
• Debiton E, Madelmont JC, Legault J, Barthomeuf C. Sanguinarine-induced apoptosis is associated with an early and severe cellular glutathione depletion. Cancer Chemother Pharmacol 2003;51:474–82.
   PubMed Web of Science ®Google Scholar
• Anderson KW, Coll RJ, Murphy AJ. Inhibition of skeletal muscle sarcoplasmic reticulum CaATPase activity by calmidazolium. J Biol Chem 1984;259:11487–90.
   PubMed Web of Science ®Google Scholar
• Gietzen K. Comparison of the calmodulin antagonists compound 48/80 and calmidazolium. Biochem J 1983;216:611–6.
   PubMed Web of Science ®Google Scholar
• Garcia-Marchan Y, Sojo F, Rodriguez E, et al. Trypanosoma cruzi calmodulin: cloning, expression and characterization. Exp Parasitol 2009;123:326–33.
   PubMed Web of Science ®Google Scholar
• Terentis AC, Freewan M, Sempértegui Plaza TS, et al. The selenazal drug Ebselen potently inhibits indoleamine 2,3-dioxygenase by targeting enzyme cysteine residues. Biochemistry 2010;49:591–600.
   PubMed Web of Science ®Google Scholar
• Lu J, Vodnala SK, Gustavsson AL, et al. Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei. J Biol Chem 2013;288:27456–68.
   PubMed Web of Science ®Google Scholar
• Joice AC, Harris MT, Kahney EW, et al. Exploring the mode of action of Ebselen in Trypanosoma brucei hexokinase inhibition. Int J Parasitol Drugs Drug Resist 2013;3:154–60.
   PubMed Web of Science ®Google Scholar
• Sharlow ER, Lyda TA, Dodson HC, et al. A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity. PLoS Negl Trop Dis 2010;4:e659.
   PubMed Web of Science ®Google Scholar
• Yamaguchi T, Sano K, Takakura K, et al. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen study group. Stroke 1998;29:12–7.
   PubMed Web of Science ®Google Scholar
• Masaki C, Sharpley AL, Cooper CM, et al. Effects of the potential lithium-mimetic, Ebselen, on impulsivity and emotional processing. Psychopharmacology (Berl) 2016;233:2655–61.
   PubMed Web of Science ®Google Scholar
• Singh N, Sharpley AL, Emir UE, et al. Effect of the putative lithium mimetic Ebselen on brain myo-inositol, sleep, and emotional processing in humans. Neuropsychopharmacology 2016;41:1768–78.
   PubMed Web of Science ®Google Scholar
• Kil J, Lobarinas E, Spankovich C, et al. Safety and efficacy of Ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2017;390:969–79.
   PubMed Web of Science ®Google Scholar
• Young J, Kima PE. The Leishmania parasitophorous vacuole membrane at the parasite–host interface. Yale J Biol Med 2019;92:511–21.
   PubMed Web of Science ®Google Scholar
• Antoine JC, Prina E, Jouanne C, Bongrand P. Parasitophorous vacuoles of Leishmania amazonensis-infected macrophages maintain an acidic pH. Infect Immun 1990;58:779–87.
   PubMed Web of Science ®Google Scholar
• Alice JI, Bellera CL, Benítez D, et al. Ensemble learning application to discover new trypanothione synthetase inhibitors. Mol Divers 2021;25:1361–73.
   PubMed Web of Science ®Google Scholar