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Toxoplasma gondii cathepsin L is the primary target of the invasion-inhibitory compound morpholinurea-leucyl-homophenyl-vinyl sulfone phenyl.

Larson ET, Parussini F, Huynh MH, Giebel JD, Kelley AM, Zhang L, Bogyo M, Merritt EA, Carruthers VB
J Biol Chem 284 26839-50 (2009)
Cited: 44 times
EuropePMC logo PMID: 19596863

Abstract

The protozoan parasite Toxoplasma gondii relies on post-translational modification, including proteolysis, of proteins required for recognition and invasion of host cells. We have characterized the T. gondii cysteine protease cathepsin L (TgCPL), one of five cathepsins found in the T. gondii genome. We show that TgCPL is the primary target of the compound morpholinurea-leucyl-homophenyl-vinyl sulfone phenyl (LHVS), which was previously shown to inhibit parasite invasion by blocking the release of invasion proteins from microneme secretory organelles. As shown by fluorescently labeled LHVS and TgCPL-specific antibodies, TgCPL is associated with a discrete vesicular structure in the apical region of extracellular parasites but is found in multiple puncta throughout the cytoplasm of intracellular replicating parasites. LHVS fails to label cells lacking TgCPL due to targeted disruption of the TgCPL gene in two different parasite strains. We present a structural model for the inhibition of TgCPL by LHVS based on a 2.0 A resolution crystal structure of TgCPL in complex with its propeptide. We discuss possible roles for TgCPL as a protease involved in the degradation or limited proteolysis of parasite proteins involved in invasion.

Articles - 3f75 mentioned but not cited (7)

  1. Toxoplasma gondii cathepsin L is the primary target of the invasion-inhibitory compound morpholinurea-leucyl-homophenyl-vinyl sulfone phenyl. Larson ET, Parussini F, Huynh MH, Giebel JD, Kelley AM, Zhang L, Bogyo M, Merritt EA, Carruthers VB. J Biol Chem 284 26839-26850 (2009)
  2. Lessons from high-throughput protein crystallization screening: 10 years of practical experience. Luft JR, Snell EH, Detitta GT. Expert Opin Drug Discov 6 465-480 (2011)
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  4. The structure of the cysteine protease and lectin-like domains of Cwp84, a surface layer-associated protein from Clostridium difficile. Bradshaw WJ, Kirby JM, Thiyagarajan N, Chambers CJ, Davies AH, Roberts AK, Shone CC, Acharya KR. Acta Crystallogr D Biol Crystallogr 70 1983-1993 (2014)
  5. Molecular cloning and anti-invasive activity of cathepsin L propeptide-like protein from Calotropis procera R. Br. against cancer cells. Kwon CW, Yang H, Yeo S, Park KM, Jeong AJ, Lee KW, Ye SK, Chang PS. J Enzyme Inhib Med Chem 33 657-664 (2018)
  6. Discovery and Optimization of Triazine Nitrile Inhibitors of Toxoplasma gondii Cathepsin L for the Potential Treatment of Chronic Toxoplasmosis in the CNS. Zwicker JD, Smith D, Guerra AJ, Hitchens JR, Haug N, Vander Roest S, Lee P, Wen B, Sun D, Wang L, Keep RF, Xiang J, Carruthers VB, Larsen SD. ACS Chem Neurosci 11 2450-2463 (2020)
  7. Optimization of dipeptidic inhibitors of cathepsin L for improved Toxoplasma gondii selectivity and CNS permeability. Zwicker JD, Diaz NA, Guerra AJ, Kirchhoff PD, Wen B, Sun D, Carruthers VB, Larsen SD. Bioorg Med Chem Lett 28 1972-1980 (2018)


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  2. Characterization of a novel organelle in Toxoplasma gondii with similar composition and function to the plant vacuole. Miranda K, Pace DA, Cintron R, Rodrigues JC, Fang J, Smith A, Rohloff P, Coelho E, de Haas F, de Souza W, Coppens I, Sibley LD, Moreno SN. Mol Microbiol 76 1358-1375 (2010)
  3. Cathepsin L occupies a vacuolar compartment and is a protein maturase within the endo/exocytic system of Toxoplasma gondii. Parussini F, Coppens I, Shah PP, Diamond SL, Carruthers VB. Mol Microbiol 76 1340-1357 (2010)
  4. Toxoplasma gondii ingests and digests host cytosolic proteins. Dou Z, McGovern OL, Di Cristina M, Carruthers VB. mBio 5 e01188-14 (2014)
  5. Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection. Di Cristina M, Dou Z, Lunghi M, Kannan G, Huynh MH, McGovern OL, Schultz TL, Schultz AJ, Miller AJ, Hayes BM, van der Linden W, Emiliani C, Bogyo M, Besteiro S, Coppens I, Carruthers VB. Nat Microbiol 2 17096 (2017)
  6. The parasite Toxoplasma sequesters diverse Rab host vesicles within an intravacuolar network. Romano JD, Nolan SJ, Porter C, Ehrenman K, Hartman EJ, Hsia RC, Coppens I. J Cell Biol 216 4235-4254 (2017)
  7. Novel insights into the composition and function of the Toxoplasma IMC sutures. Chen AL, Moon AS, Bell HN, Huang AS, Vashisht AA, Toh JY, Lin AH, Nadipuram SM, Kim EW, Choi CP, Wohlschlegel JA, Bradley PJ. Cell Microbiol 19 (2017)
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  9. Toxoplasma gondii Vps11, a subunit of HOPS and CORVET tethering complexes, is essential for the biogenesis of secretory organelles. Morlon-Guyot J, Pastore S, Berry L, Lebrun M, Daher W. Cell Microbiol 17 1157-1178 (2015)
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  11. Novel N-benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway. Fomovska A, Huang Q, El Bissati K, Mui EJ, Witola WH, Cheng G, Zhou Y, Sommerville C, Roberts CW, Bettis S, Prigge ST, Afanador GA, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Pieroni M, Stec J, Muench SP, Rice DW, Kozikowski AP, McLeod R. Antimicrob Agents Chemother 56 2666-2682 (2012)
  12. Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii. Daher W, Morlon-Guyot J, Sheiner L, Lentini G, Berry L, Tawk L, Dubremetz JF, Wengelnik K, Striepen B, Lebrun M. Cell Microbiol 17 559-578 (2015)
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  14. Eimeripain, a cathepsin B-like cysteine protease, expressed throughout sporulation of the apicomplexan parasite Eimeria tenella. Rieux A, Gras S, Lecaille F, Niepceron A, Katrib M, Smith NC, Lalmanach G, Brossier F. PLoS One 7 e31914 (2012)
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  16. Role of Toxoplasma gondii Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance. Kannan G, Di Cristina M, Schultz AJ, Huynh MH, Wang F, Schultz TL, Lunghi M, Coppens I, Carruthers VB. mBio 10 e01324-19 (2019)
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  18. An ortholog of Plasmodium falciparum chloroquine resistance transporter (PfCRT) plays a key role in maintaining the integrity of the endolysosomal system in Toxoplasma gondii to facilitate host invasion. Thornton LB, Teehan P, Floyd K, Cochrane C, Bergmann A, Riegel B, Stasic AJ, Di Cristina M, Moreno SNJ, Roepe PD, Dou Z. PLoS Pathog 15 e1007775 (2019)
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  22. Inhibition of cathepsin S reduces allogeneic T cell priming but not graft-versus-host disease against minor histocompatibility antigens. Fujii H, Ivison SM, Shimizu H, Kajiwara R, Kariminia A, Yan M, Dutz JP, Schultz KR. Biol Blood Marrow Transplant 18 546-556 (2012)
  23. Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis. Chaparro JD, Cheng T, Tran UP, Andrade RM, Brenner SBT, Hwang G, Cohn S, Hirata K, McKerrow JH, Reed SL. PLoS One 13 e0193982 (2018)
  24. Determination of Chemical Inhibitor Efficiency against Intracellular Toxoplasma Gondii Growth Using a Luciferase-Based Growth Assay. Key M, Bergmann A, Micchelli C, Thornton LB, Millard S, Dou Z. J Vis Exp (2020)
  25. Cloning and characterization of a basic cysteine-like protease (cathepsin L1) expressed in the gut of larval Diaprepes abbreviatus L. (Coleoptera: Curculionidae). Ben-Mahmoud S, Ramos JE, Shatters RG, Rougé P, Powell CA, Smagghe G, Borovsky D. J Insect Physiol 72 1-13 (2015)
  26. Identification and characterization of a cathepsin-L-like peptidase in Eimeria tenella. Liu R, Ma X, Liu A, Zhang L, Cai J, Wang M. Parasitol Res 113 4335-4348 (2014)
  27. Identification and characteristics of a cathepsin L-like cysteine protease from Clonorchis sinensis. Ma C, Liang K, Tang L, He S, Liu X, He M, Li Y. Parasitol Res 118 829-835 (2019)
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