as-reaserch1 200x154Trypanosoma brucei (BS stumpy form on millipore filter). Credit: WHO/TDR/Vickerman
as-reaserch2 200x130Photomicrograph of Trypanosoma brucei gambienese. Credit: WHO/TDR

The CDIPD has had a long-standing interest in the biological function of the trypanosome proteases and we continue to explore proteases as a potential target class as well as to gain better understanding of key trypanosome pathways.

In collaboration with Jack Taunton's laboratory at UCSF, we have also been probing the biology of several Trypanosoma brucei kinases. Through these efforts we have identified several possible drug targets. We are currently focusing on screening of these kinases, as well as whole parasite screening of kinase inhibitor libraries.

We continue to do a significant amount of whole parasite screening to identify compounds that may be relevant hits for lead development. Compounds with anti-trypansomal activity may also be useful tools to explore parasite biology and identify new targets and pathways of interest. Some of our collaborations in this area include a collaboration in natural products chemistry with Roger Linington at UCSC. This collaboration has continued to identify compounds that may become promising tools and leads. We also are collaborating with researchers at Stanford to test FDA approved compounds for activity against T. brucei with the goal of repurposing for use in treatment of this disease. Finally, we continue to have numerous small collaborations, such as those with Pharmadyn testing focused compound libraries against T. brucei to identify possible new lead series to pursue in our drug development efforts.

 

pipeline 720x38
  • Proteases
  • Kinases
  • Utilizing tool anti-trypansomal compounds to explore potential targets and pathways
  • Targeting whole parasite:
  1. Stanford/FDA approved compounds
  2. Natural Products – Phil Crews and Roger Linington/UCSC
  • Kinase targeted libraries
  • Screening of novel kinase targets
  • Novel kinase target hit-to-lead chemistry
 

PUBLICATIONS

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.

Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei [corrected]. Elife. 2013 Jul 9;2:e00712. doi: 10.7554/eLife.00712. Erratum in: Elife. 2013;e01214. Nishino M, Choy JW, Gushwa NN, Oses-Prieto JA, Koupparis K, Burlingame AL, Renslo AR, McKerrow JH, Taunton J.

Examination of the mode of action of the almiramide family of natural products against the kinetoplastid parasite Trypanosoma brucei. J Nat Prod. 2013 Apr 26;76(4):630-41. doi: 10.1021/np300834q. Epub 2013 Feb 27. Sanchez LM, Knudsen GM, Helbig C, De Muylder G, Mascuch SM, Mackey ZB, Gerwick L, Clayton C, McKerrow JH, Linington RG.

A global comparison of the human and T. brucei degradomes gives insights about possible parasite drug targets. PLoS Negl Trop Dis. 2012;6(12):e1942. doi: 10.1371/journal.pntd.0001942. Epub 2012 Dec 6. Mashiyama ST, Koupparis K, Caffrey CR, McKerrow JH, Babbitt PC.

Hit-to-lead development of the chamigrane endoperoxide merulin A for the treatment of African sleeping sickness. PLoS One. 2012;7(9):e46172. doi: 10.1371/journal.pone.0046172. Epub 2012 Sep 27. Navarro G, Chokpaiboon S, De Muylder G, Bray WM, Nisam SC, McKerrow JH, Pudhom K, Linington RG.

Antitrypanosomal and cysteine protease inhibitory activities of alkyldiamine cryptolepine derivatives. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6256-60. doi: 10.1016/j.bmcl.2012.07.104. Epub 2012 Aug 15. Lavrado J, Mackey Z, Hansell E, McKerrow JH, Paulo A, Moreira R.

Trypanosoma brucei: chemical evidence that cathepsin L is essential for survival and a relevant drug target. Int J Parasitol. 2012 May 1;42(5):481-8. doi: 10.1016/j.ijpara.2012.03.009. Epub 2012 Apr 24. Steverding D, Sexton DW, Wang X, Gehrke SS, Wagner GK, Caffrey CR.

High-throughput analysis of an RNAi library identifies novel kinase targets in Trypanosoma brucei. Chem Biol Drug Des. 2011 Sep;78(3):454-63. doi: 10.1111/j.1747-0285.2011.01156.x. Epub 2011 Jul 14. Mackey ZB, Koupparis K, Nishino M, 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.

Mining a cathepsin inhibitor library for new antiparasitic drug leads. PLoS Negl Trop Dis. 2011 May 3;5(5):e1023. doi: 10.1371/journal.pntd.0001023. Ang KK, Ratnam J, Gut J, Legac J, Hansell E, Mackey ZB, Skrzypczynska KM, Debnath A, Engel JC, Rosenthal PJ, McKerrow JH, Arkin MR, Renslo AR.

Discovery of novel benzoxaborole-based potent antitrypanosomal agents. ACS Med Chem Lett. 2010 Jul 8;1(4):165-9. doi: 10.1021/ml100013s. Ding D, Zhao Y, Meng Q, Xie D, Nare B, Chen D, Bacchi CJ, Yarlett N, Zhang YK, Hernandez V, Xia Y, Freund Y, Abdulla M, Ang KH, Ratnam J, McKerrow JH, Jacobs RT, Zhou H, Plattner JJ.

Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB. J Med Chem. 2010 Jan 14;53(1):52-60. doi: 10.1021/jm901069a. Mott BT, Ferreira RS, Simeonov A, Jadhav A, Ang KK, Leister W, Shen M, Silveira JT, Doyle PS, Arkin MR, McKerrow JH, Inglese J, Austin CP, Thomas CJ, Shoichet BK, Maloney DJ.

Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6218-21. doi: 10.1016/j.bmcl.2009.08.098. Epub 2009 Sep 3. Bryant C, Kerr ID, Debnath M, Ang KK, Ratnam J, Ferreira RS, Jaishankar P, Zhao D, Arkin MR, McKerrow JH, Brinen LS, Renslo AR.

Structure-guided development of selective TbcatB inhibitors. J Med Chem. 2009 Oct 22;52(20):6489-93. doi: 10.1021/jm900908p. Mallari JP, Shelat AA, Kosinski A, Caffrey CR, Connelly M, Zhu F, McKerrow JH, Guy RK.

Vinyl sulfones as antiparasitic agents and a structural basis for drug design. J Biol Chem. 2009 Sep 18;284(38):25697-703. doi: 10.1074/jbc.M109.014340. Epub 2009 Jul 20. Kerr ID, Lee JH, Farady CJ, Marion R, Rickert M, Sajid M, Pandey KC, Caffrey CR, Legac J, Hansell E, McKerrow JH, Craik CS, Rosenthal PJ, Brinen LS.

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.

The marine sponge Diacarnus bismarckensis as a source of peroxiterpene inhibitors of Trypanosoma brucei, the causative agent of sleeping sickness. J Nat Prod. 2009 Feb 27;72(2):218-22. doi: 10.1021/np800711a. Rubio BK, Tenney K, Ang KH, Abdulla M, Arkin M, McKerrow JH, Crews P.

RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model. PLoS Negl Trop Dis. 2008 Sep 24;2(9):e298. doi: 10.1371/journal.pntd.0000298. Abdulla MH, O'Brien T, Mackey ZB, Sajid M, Grab DJ, McKerrow JH.

A parasite cysteine protease is key to host protein degradation and iron acquisition. J Biol Chem. 2008 Oct 24;283(43):28934-43. doi: 10.1074/jbc.M805824200. Epub 2008 Aug 13. O'Brien TC, Mackey ZB, Fetter RD, Choe Y, O'Donoghue AJ, Zhou M, Craik CS, Caffrey CR, McKerrow JH.

Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB. Bioorg Med Chem Lett. 2008 May 1;18(9):2883-5. doi: 10.1016/j.bmcl.2008.03.083. Epub 2008 Apr 8. Mallari JP, Shelat A, Kosinski A, Caffrey CR, Connelly M, Zhu F, McKerrow JH, Guy RK.

Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB. J Med Chem. 2008 Feb 14;51(3):545-52. doi: 10.1021/jm070760l. Epub 2008 Jan 4. Mallari JP, Shelat AA, Obrien T, Caffrey CR, Kosinski A, Connelly M, Harbut M, Greenbaum D, McKerrow JH, Guy RK.

Proteases in parasitic diseases. Annu Rev Pathol. 2006;1:497-536. Review. McKerrow JH, Caffrey C, Kelly B, Loke P, Sajid M.

Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro. Antimicrob Agents Chemother. 2007 Jun;51(6):2164-72. Epub 2007 Mar 19. Caffrey CR, Steverding D, Swenerton RK, Kelly B, Walshe D, Debnath A, Zhou YM, Doyle PS, Fafarman AT, Zorn JA, Land KM, Beauchene J, Schreiber K, Moll H, Ponte-Sucre A, Schirmeister T, Saravanamuthu A, Fairlamb AH, Cohen FE, McKerrow JH, Weisman JL, May B

The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo. Kinetoplastid Biol Dis. 2007 Feb 28;6:2. Scory S, Stierhof YD, Caffrey CR, Steverding D.

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.

Discovery of trypanocidal compounds by whole cell HTS of Trypanosoma brucei. Chem Biol Drug Des. 2006 May;67(5):355-63. Mackey ZB, Baca AM, Mallari JP, Apsel B, Shelat A, Hansell EJ, Chiang PK, Wolff B, Guy KR, Williams J, McKerrow JH.

Antitrypanosomal activity of 5'-deoxy-5'-(iodomethylene)adenosine and related 6-N-cyclopropyladenosine analogues. J Med Chem. 2006 Mar 23;49(6):2096-102. Rapp M, Haubrich TA, Perrault J, Mackey ZB, McKerrow JH, Chiang PK, Wnuk SF.

Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Bioorg Med Chem Lett. 2006 May 15;16(10):2753-7. Epub 2006 Mar 3. Vicik R, Hoerr V, Glaser M, Schultheis M, Hansell E, McKerrow JH, Holzgrabe U, Caffrey CR, Ponte-Sucre A, Moll H, Stich A, Schirmeister T.

Discovery of potent thiosemicarbazone inhibitors of rhodesain and cruzain. Bioorg Med Chem Lett. 2005 Jan 3;15(1):121-3. Fujii N, Mallari JP, Hansell EJ, Mackey Z, Doyle P, Zhou YM, Gut J, Rosenthal PJ, McKerrow JH, Guy RK.

A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei. J Biol Chem. 2004 Nov 12;279(46):48426-33. Epub 2004 Aug 23. Mackey ZB, O'Brien TC, Greenbaum DC, Blank RB, McKerrow JH.

Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi. J Med Chem. 2004 Jun 3;47(12):3212-9. Greenbaum DC, Mackey Z, Hansell E, Doyle P, Gut J, Caffrey CR, Lehrman J, Rosenthal PJ, McKerrow JH, Chibale K.

Screening of acyl hydrazide proteinase inhibitors for antiparasitic activity against Trypanosoma brucei. Int J Antimicrob Agents. 2002 Mar;19(3):227-31. Erratum in: Int J Antimicrob Agents. 2005 Jul;26(1):100. Nkemgu-Njinkeng, Joseph [corrected to Nkemngu, Njinkeng Joseph]. Int J Antimicrob Agents. 2005 Nov;26(5):424. Caffrey CR, Schanz M, Nkemngu NJ, Brush M, Hansell E, Cohen FE, Flaherty TM, McKerrow JH, Steverding D.

Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Mol Biochem Parasitol. 2001 Nov;118(1):61-73. Caffrey CR, Hansell E, Lucas KD, Brinen LS, Alvarez Hernandez A, Cheng J, Gwaltney SL 2nd, Roush WR, Stierhof YD, Bogyo M, Steverding D, McKerrow JH.

Cysteine proteinases of trypanosome parasites: novel targets for chemotherapy. Curr Drug Targets. 2000 Sep;1(2):155-62. Review. Caffrey CR, Scory S, Steverding D.

Aryl ureas represent a new class of anti-trypanosomal agents. Chem Biol. 2000 Sep;7(9):733-42. Du X, Hansell E, Engel JC, Caffrey CR, Cohen FE, 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.

Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei brucei. Exp Parasitol. 1999 Apr;91(4):349-55. Troeberg L, Morty RE, Pike RN, Lonsdale-Eccles JD, Palmer JT, McKerrow JH, Coetzer TH.

Trypanosoma brucei: killing of bloodstream forms in vitro and in vivo by the cysteine proteinase inhibitor Z-phe-ala-CHN2. Exp Parasitol. 1999 Apr;91(4):327-33. Scory S, Caffrey CR, Stierhof YD, Ruppel A, Steverding D.

High level expression in Escherichia coli of soluble, enzymatically active schistosomal hypoxanthine/guanine phosphoribosyltransferase and trypanosomal ornithine decarboxylase. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2500-4. Craig SP 3rd, Yuan L, Kuntz DA, McKerrow JH, Wang CC. Craig