Leishmania parasites, coloured scanning electron micrograph. Credit: visualphotos.com
Our work on Leishmania is focused on two main areas—identification of new therapeutic targets and screening of compound libraries. Research efforts focused on the role of the protease subtilisin showed that knockout of subtilisin slows down parasite growth and impacts the trypanothione pathway. These data are compelling from a drug discovery standpoint, as there is already a validated drug target in this pathway, and indicates further exploration of pathway members as drug targets is warranted. Our work has also demonstrated essentiality of CYP51 in Leishmania donovani validating sterol 14-demethylation as therapeutic target for visceral leishmaniasis.
Screening efforts at the CDIPD were initiated in July 2009 with the objective of developing a high throughput assay format capable of screening the activity of small molecules against the intracellular amastigote form of Leishmania parasites. This assay, now developed, is enabling efficient screening of chemical libraries with the most relevant form of the parasite with respect to human disease. We are now identifying leads both for drug development and as tools for further biological exploration of the parasite. With this assay we expect to broaden our collaborations with industrial partners to have access to a large diversity of small molecules and to share an assay more relevant and more adapted to the discovery of active compounds against an intracellular parasite.
Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. PLoS Negl Trop Dis. 2015 Mar;9(3):e0003588. doi: 10.1371/journal.pntd.0003588. McCall LI, El Aroussi A, Choi JY, Vieira DF, De Muylder G, Johnston JB, Chen S, Kellar D, Siqueira-Neto JL, Roush WR, Podust LM, McKerrow JH.
Determinants of disease phenotype in trypanosomatid parasites. Trends Parasitol. 2014 Jul;30(7):342-9. doi: 10.1016/j.pt.2014.05.001. Epub 2014 Jun 16. Review. McCall LI, McKerrow JH.
A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Negl Trop Dis. 2011 Jul;5(7):e1253. doi: 10.1371/journal.pntd.0001253. Epub 2011 Jul 19. De Muylder G, Ang KK, Chen S, Arkin MR, Engel JC, McKerrow JH.
Cysteine peptidases of kinetoplastid parasites. Adv Exp Med Biol. 2011;712:84-99. doi: 10.1007/978-1-4419-8414-2_6. Review. Caffrey CR, Lima AP, Steverding D.
The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion. J Biol Chem. 2011 Jan 7;286(1):429-40. doi: 10.1074/jbc.M110.138313. Epub 2010 Oct 20. Swenerton RK, Zhang S, Sajid M, Medzihradszky KF, Craik CS, Kelly BL, McKerrow JH.
Leishmania subtilisin is a maturase for the trypanothione reductase system and contributes to disease pathology. J Biol Chem. 2010 Oct 8;285(41):31120-9. doi: 10.1074/jbc.M110.114462. Epub 2010 Jul 30. Swenerton RK, Knudsen GM, Sajid M, Kelly BL, McKerrow JH.
Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines. PLoS Negl Trop Dis. 2010 Mar 30;4(3):e648. doi: 10.1371/journal.pntd.0000648. Zhang S, Kim CC, Batra S, McKerrow JH, Loke P.
Kinetoplastid papain-like cysteine peptidases. Mol Biochem Parasitol. 2009 Sep;167(1):12-9. doi: 10.1016/j.molbiopara.2009.04.009. Epub 2009 May 3. Review. Caffrey CR, Steverding D.
Metal compounds for the treatment of parasitic diseases. J Inorg Biochem. 2008 Oct;102(10):1839-45. doi: 10.1016/j.jinorgbio.2008.05.010. Epub 2008 Jun 4. Erratum in: J Inorg Biochem. 2009 May;103(5):869. Fricker SP, Mosi RM, Cameron BR, Baird I, Zhu Y, Anastassov V, Cox J, Doyle PS, Hansell E, Lau G, Langille J, Olsen M, Qin L, Skerlj R, Wong RS, Santucci Z, McKerrow JH.
Proteases in parasitic diseases. Annu Rev Pathol. 2006;1:497-536. Review. McKerrow JH, Caffrey C, Kelly B, Loke P, Sajid M.
Cysteine proteinase inhibitors as therapy for parasitic diseases: advances in inhibitor design. Mini Rev Med Chem. 2006 Sep;6(9):1025-32. Review. Steverding D, Caffrey CR, Sajid M.
Leishmania tropica: cysteine proteases are essential for growth and pathogenicity. Exp Parasitol. 2004 Mar-Apr;106(3-4):158-63. Mahmoudzadeh-Niknam H, McKerrow JH.
Cysteine protease inhibitors as chemotherapy: lessons from a parasite target. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11015-22. Selzer PM, Pingel S, Hsieh I, Ugele B, Chan VJ, Engel JC, Bogyo M, Russell DG, Sakanari JA, McKerrow JH.
Cysteine protease inhibitors as chemotherapy for parasitic infections. Bioorg Med Chem. 1999 Apr;7(4):639-44. Review. McKerrow JH, Engel JC, Caffrey CR.
Protease trafficking in two primitive eukaryotes is mediated by a prodomain protein motif. J Biol Chem. 1999 Jun 4;274(23):16249-56. Huete-Pérez JA, Engel JC, Brinen LS, Mottram JC, McKerrow JH.
Expression and alteration of the S2 subsite of the Leishmania major cathepsin B-like cysteine protease. Biochem J. 1999 May 15;340 ( Pt 1):113-7. Chan VJ, Selzer PM, McKerrow JH, Sakanari JA.
Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem. 1998 Dec;6(12):2477-94. Scheidt KA, Roush WR, McKerrow JH, Selzer PM, Hansell E, Rosenthal PJ.
Leishmania major: molecular modeling of cysteine proteases and prediction of new nonpeptide inhibitors. Exp Parasitol. 1997 Nov;87(3):212-21. Selzer PM, Chen X, Chan VJ, Cheng M, Kenyon GL, Kuntz ID, Sakanari JA, Cohen FE, McKerrow JH.