Dr. Mohammed Sajid

Research interest

I am part of a group, led by Shahid Khan, who is interested in generated genetically attenuated parasites, with an end aim to producing a whole organism anti-malaria vaccine.  It has been shown many decades ago that whole malaria parasite irradiation can indeed confer immunological protection if the parasite can travel from the insect host to the human liver, however, generating reproducible and reagent quantities of parasite material has proved arduous. The group’s work hopes to emulate and improve upon previous findings by discreetly targeting liver stage specific genes – this approach has already been fruitful with a number of genes in house that show good vaccine potential, however, with these reagents some parasites were still able to complete the liver stage of the malaria lifecycle and so produce an infection; our aim is to generate a parasite that is completely blocked in the liver, and also provides immunological protection. 

Background:  Prior to my position at LUMC I was involved in many aspects of protein catabolism in parasitic organisms. I was principally interested in parasite peptidase biochemistry, particularly in the identification, characterization and biological validation of parasite enzymes as rational targets for selective chemotherapeutic intervention. My research interests have led me to work with several parasitic protozoa and helminths, including, malaria (see  The Synaptic Leap ), Giardia, Cryptosporidium, Entamoeba,Trypanosoma, Leishmania and numerous parasitic nematodes and flukes. Proteases of interest were cloned and heterologously expressed to generate reagent quantities of active enzyme for use in substrate and inhibitor screens as well as crystallography.  Specific inhibitors or probes can subsequently be used to delineate the discrete in vivo biological function of the protease of interest. In addition to the aforementioned area of research – I was also very interested in the detailed chemical mechanism of substrate and inhibitor binding and hydrolysis- which provide detailed valuable insights in how drugs interact with the enzyme’s active site and so aid the design of more potent and selective anti-parasite biocides.

Publications

• Lopez Quezada LA, Sajid M, Lim KC, McKerrow JH. A blood fluke serine protease inhibitor regulates an endogenous larval elastase. Journal of Biological Chemistry 2011. in press
• Lin JW, Annoura T, Sajid M, Chevalley-Maurel S, Ramesar J, Klop O, Franke-Fayard BM, Janse CJ, Khan SM. A Novel 'Gene Insertion/Marker Out' (GIMO) Method for Transgene Expression and Gene Complementation in Rodent Malaria Parasites. PLoS One. 2011;6(12)e29289.
• Swenerton RK, Knudsen GM, Sajid M, Kelly BL, McKerrow JH. Leishmania subtilisin is a maturase for the trypanothione reductase system and contributes to disease pathology Journal of Biological Chemstry. in press
• Abodeely M, DuBois KN, Hehl A, Stefanic , Sajid M, deSouza W, Attias M, J Engel JC, Hsieh I, Fetter RD, and McKerrow JH (2009). A contiguous compartment functions as ER and endosome/lysosome in Giardia lamblia. Eukaryotic Cell. 8(11), 1665-76.
• Kerr ID, Hyun Lee J, Farady CJ, Marion R, Rickert M, Sajid M, Pandey KC,Caffrey CR, Legac J, Hansell E, McKerrow JH, Craik CS, Rosenthal PJ and Brinen LS (2009). Vinyl sulfones as antiparasitic agents: A structural basis for drug design. Journal of Biological Chemistry. 284, 25697-703.
• M Berriman, B Haas, PT LoVerde, RA Wilson,GP. Dillon, GC Cerqueira, ST Mashiyama, B Al-Lazikani, LF Andrade, PD Ashton, MA Aslett, D Bartholomeu, G Blandin, CR Caffrey, Richard M.R. Coulson, TA Day, Art Delcher, R De Marco, A Djikeng, T Eyre, J Gamble, E Ghedin, Y Gu, C Hertz-Fowler, H Hirai, Y Hirai, J Gamble, R Houston, A IvenS, D Johnston, D Lacerda, C Macedo, AZ Neto, Z Ning, G Oliveira, JP Overington, J Parkhill, M Pertea, AV Protasio, MA Quail, J Rogers, M Sajid, SL Salzberg, M Stanke, AR Tivey, O White, DL Williams, J Wortman, W Wu, M Zamanian, CM Fraser-Liggett, BG Barrell, NM El-Sayed. The Genome of the blood fluke Schistosoma mansoni. (2009). Nature. 460(7253);352-358.
• Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS (2009). Crystal structures of two cysteine proteases, Falcipain 2 and Falcipain 3, bound to small molecule inhibitors provide a molecular map of the enzymes active sites. Journal of Medicinal Chemistry. 52(3);852-857.
• Pungerèar JR, Dolinar M, Cagliè D, Vasiljeva O, Turk D, Sajid M, Bogyo M, Turk V, Turk B. Autocatalytic processing of procathepsin B is triggered by proenzyme activity. FEBS Letters. 276(3);660-668.
• Abdulla M, O'Brien T, Mackey ZB, Sajid M, Grab DJ, McKerrow JH (2008). RNA Interference of Trypanosoma brucei Cathepsin B and L Affects Disease Progression in a Mouse Model. PLoS. Neglected Tropical Diseases 2(9):e298 .
• Kongkerd N, Uparanukraw P, Morakote N, Sajid M, McKerrow JH. Identification and characterization of a cathepsin L-like cysteine protease from Gnathostoma spinigerum. Molecular and Biochemical Parasitology, 2008;160(2):129-137.
• Identification of the Major Cysteine Protease of Giardia and its Role in Encystation DuBois KN, Abodeely M, Sakanari J, Craik CS, Lee M , McKerrow JH, Sajid M. Journal of Biological Chemistry.2008;283(26)18024-18031.
• Dvorak J, Mashiyama S, Braschi S, Sajid M, Knudsen GM, Hansell E, Lim KC, Hsieh I, Bahgat M, Mackenzie B, Medzihradszky KF, Babbitt PC, Caffrey CR, McKerrow JH. Differential use of protease families for invasion by schistosome cercariae. Biochimie. 2008;90:345-358.
• Debnath A, Tashker JS, Sajid M, Mckerrow JH. The transcriptional and secretory responses of Entamoeba histolytica to mucins, epithelial cells and bacteria. International Journal of Parasitology. 2007;37(8-9):897-906.
• Sojka D, Hajducek O, Dvorák J, Sajid M, Franta Z, Schneider E, Craik CS, Vancová M, Burecová V, McKerrow JH, Caffrey CR, Kopácek P. IrAE – a novel asparaginyl endopeptidase (legumain) from the gut of the hard tick Ixodes ricinus. International Journal of Parasitology 2007;37:713-724.
• Abdulla M-H, Lim KC, Sajid M, McKerrow JH, Caffrey CR. Schistosomiasis mansoni: novel chemotherapy using a cysteine protease inhibitor. PLoS Medicine. 2007;4(1):1-9.
• Delcroix M, Sajid M, Caffrey CR, Lim KC, Dvorak J, Hsieh I, Bahgat M, Dissous C, McKerrow JH. A multienzyme network functions in intestinal protein digestion by a platyhelminth parasite. Journal of Biological Chemistry. 2006;281(51):39316-29.
• Walker MJ, Rylett CM, Keen, JN, Audsley N, Sajid M, Shirras AD, Isaac RE. Proteomic identification of Drosophila melanogater male accessory gland proteins, including a pro-cathepsin and a soluble γ-glutamyl transpeptidase. Proteome Science 2006;4:9.
• Wippersteg V, Sajid M, Walshe D, Kiem D, McKerrow JH, Grevelding CG, Caffrey CR. Biolistic transformation of Schistosoma mansoni with 5' flanking regions of two peptidase gene promoter tissue-specific expression. International Journal of Parasitology 2005;35:895-910.
• Caffrey CR, Plancha L, Barinka C, Hradij M, Sajid M, McKerrow JH, Majer P, Vondrasek J. Homology modeling and SAR analysis of Schistosoma japonicum cathepsin D (SjCD) with statin inhibitors identifies a unique active site barrier of potential for the design of specific inhibitors. Biological Chemistry 2005;386(4):339-349.
• Dvorak J, Delcroix M, Rossi A, Vopalensky V, Pospisek M, Sedinova M, Mikes L, Sajid M, Sali A, McKerrow JH, Horak P, Caffrey CR. Multiple cathepsin B isoforms in schistosomula of Trichobilharzia regenti; identification, characterisation and putative role in migration and nutrition. International Journal of Parasitology 2005;35(8):895-910.
• Williamson AL, Lecchi P, Turk BE, Choe Y, Hotez PJ, McKerrow JH, Cantley LC, Sajid M, Craik CS, Loukas A. A multi-enzyme cascade of hemoglobin proteolysis in the intestine of blood-feeding hookworms. Journal of Biological Chemistry 2004;279(34):35950-7.
• Debnath A, Das P, Sajid M, McKerrow JH. Identification of genomic responses to collagen binding by trophozoites of Entamoeba histolytica. Journal of Infectious Diseases 2004;190(3):448-57.
• Sajid M, McKerrow JH, Hansell E, Mathieu MA, Lucas KD, Hsieh I, Greenbaum D, Bogyo M, Salter JP, Lim KC, Franklin C, Kim JH, Caffrey CR. Functional expression and characterization of Schistosoma mansoni cathepsin B and its trans-activation by an endogenous asparaginyl endopeptidase. Molecular and Biochemical Parasitology 2003;131(1):65-75.
• Que X, Kim SH, Sajid M, Eckmann L, Dinarello CA, McKerrow JH, Reed SL. A surface amebic cysteine proteinase inactivates interleukin-18. Infection and Immunity 2003;71(3):1274-80.
• Caffrey CR, Salter JP, Lucas KD, Khiem D, Hsieh I, Lim KC, Ruppel A, McKerrow JH, Sajid M. SmCB2, a novel tegumental cathepsin B from adult Schistosoma mansoni. Molecular and Biochemical Parasitology 2002;121(1):49-61.
• Mathieu MA, Bogyo M, Caffrey CR, Choe Y, Lee J, Chapman H, Sajid M, Craik CS, McKerrow JH. Substrate specificity of schistosome versus human legumain determined by P1-P3 peptide libraries. Molecular and Biochemical Parasitology 2002;121(1):99-105.
• Taylor HM, Triglia T, Thompson J, Sajid M, Fowler R, Wickham ME, Cowman AF, Holder AA. Plasmodium falciparum homologue of the genes for Plasmodium vivax and Plasmodium yoelii adhesive proteins, which is transcribed but not translated. Infection and Immunity 2001;69(6):3635-45.
• Caffrey CR, Mathieu MA, Gaffney AM, Salter JP, Sajid M, Lucas KD, Franklin C, Bogyo M, McKerrow JH. Identification of a cDNA encoding an active asparaginyl endopeptidase of Schistosoma mansoni and its expression in Pichia pastoris. FEBS Lett 2000;466(2-3):244-8.
• Sajid M, Withers-Martinez C, Blackman MJ. Maturation and specificity of Plasmodium falciparum subtilisin-like protease-1, a malaria merozoite subtilisin-like serine protease. Journal of Biological Chemistry 2000;275(1):631-41.
• Withers-Martinez C, Carpenter EP, Hackett F, Ely B, Sajid M, Grainger M, Blackman MJ. PCRbased gene synthesis as an efficient approach for expression of the A+T-rich malaria genome. Protein Engineering 1999;12(12):1113-20.
• Gunaratne RS, Sajid M, Ling IT, Tripathi R, Pachebat JA, Holder AA. Characterization of N-myristoyltransferase from Plasmodium falciparum. Biochemical Journal 2000;348 Pt 2:459-63.
• Hackett F, Sajid M, Withers-Martinez C, Grainger M, Blackman MJ. PfSUB-2: a second subtilisinlike protein in Plasmodium falciparum merozoites. Molecular and Biochemical Parasitology 1999;103(2):183-95.
• Blackman MJ, Fujioka H, Stafford WH, Sajid M, Clough B, Fleck SL, Aikawa M, Grainger M, Hackett F. A subtilisin-like protein in secretory organelles of Plasmodium falciparum merozoites. Journal of Biological Chemistry 1998;273(36):23398-409.
• Isaac R, Schoofs L, Williams TA, Veelaert D, Sajid M, Corvol P, Coates D. A novel peptideprocessing activity of insect peptidyl-dipeptidase A (angiotensin I-converting enzyme): the hydrolysis of lysyl-arginine and arginyl-arginine from the C-terminus of an insect prohormone peptide. Biochemical Journal 1998;330 ( Pt 1):61-5.
• Sajid M, Isaac RE, Harrow ID. Purification and properties of a membrane aminopeptidase from Ascaris suum muscle that degrades neuropeptides AF1 and AF2. Molecular and Biochemical Parasitology 1997;89(2):225-34.
• Isaac RE, Williams TA, Sajid M, Corvol P, Coates D. Cleavage of arginyl-arginine and lysylarginine from the C-terminus of pro-hormone peptides by human germinal angiotensin I-converting enzyme (ACE) and the C-domain of human somatic ACE. Biochemical Journal 1997;328(Pt 2):587-91.
• Sajid M, Keating C, Holden-Dye L, Harrow ID, Isaac RE. Metabolism of AF1 (KNEFIRF-NH2) in the nematode, Ascaris suum, by aminopeptidase, endopeptidase and deamidase enzymes. Molecular and Biochemical Parasitology 1996;75(2):159-68.
• Lamango NS, Sajid M, Isaac RE. The endopeptidase activity and the activation by Cl- of angiotensin-converting enzyme are evolutionarily conserved: purification and properties of an angiotensin-converting enzyme from the housefly, Musca domestica. Biochemical Journal 1996;314(Pt 2):639-46.
• Sajid M, Isaac RE. Identification and properties of a neuropeptide-degrading endopeptidase (neprilysin) of Ascaris suum muscle. Parasitology 1995;111(Pt 5):599-608.
• Sajid M, Isaac RE. Metabolism of AF1 (KNEFIRF-NH2) in the nematode Ascaris suum. Biochemical Society Transaction 1994;22(3):293S.
• Kemp RB, Stephansen C, Sajid M and Meredith RWJ. The calorimetric-responsimetric ratio: its potential as a cytotoxicity test. Alternative to Laboratory Animals 1994;22:364-377.
• Sajid M and RE. Isaac. Neuropeptide metabolism in nematodes: Properties of a membrane-bound aminopeptidase and endopeptidase. Journal of Cellular Biochemistry 1993;17C:119.

Reviews:

• Kaczanowski S, Sajid M, Reece SE. Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites. Parasites and Vectors. 2011 Mar 25;4(1):44.
• Pollitt LC, Colegrave N, Khan SM, Sajid M, Reece SE. Investigating the evolution of apoptosis in malaria parasites: the importance of ecology. Parasites and Vectors. 2010 Nov 16;3:105.
• Atkinson HJ, Babbitt PC, and Sajid M. The global cysteine peptidase landscape in parasites. Trends in Parasitology. 2009. 25(12), 573-81.
• DuBois K, Abodeely M, Sajid M and McKerrow JH. Cysteine Protease of Giardia lamblia. Journal of Experimental Parasitology 2006;99(4):313-6.
• McKerrow JH, Caffrey C, Kelly B, Loke P and Sajid M. Proteases in Parasitic Diseases. Annual Review of Pathology; Mechanism of Disease 2006, volume 1. 497-536.
• Sterverding D, Caffrey C and Sajid M. Cysteine Proteinase Inhibitors as Therapy for Parasitic Diseases: Advances in Inhibitor Design. Mini Reviews in Medicinal Chemistry 2006;6(9):1025-32.
• Caffrey CR, McKerrow JH, Salter JP, Sajid M. Blood 'N' Guts: an Update on Schistosome Digestive Peptidases. Trends in Parasitology 2004;20(5):241-8.
• Mottram JC, Helms MJ, Coombs GH, Sajid M. Clan CD Cysteine Peptidases of Parasitic Protozoa. Trends in Parasitology 2003;19(4):182-7.
• Sajid M, McKerrow JH. Cysteine Proteases of Parasitic Organisms. Molecular and Biochemical Parasitology 2002;120(1):1-21. 

Book chapters:

• Sajid M, Robertson S, Brinen LS, McKerrow JH. Cruzain, the Path from target validation to the clinic. In. Cysteine Proteases of Pathogenic Organisms. Ed. Robinson M, Dalton J. Landes Bioscience and Springer Science.
• M Sajid, M Blackman, P Doyle, C He, KM Land, C Lobo, Z Mackey, M Ndao, SL. Reed, B Shiels, R Swenerton, W Weir. Proteases of Parasitic Protozoa - Current Status and Validation. In. Drug Discovery in Infectious Diseases. From Molecular Targets to Drug Candidate (Ed. Selzer). 2008.
• Doyle PS, Sajid M, O’Brien T, DuBois K, Enge JC, Mackey ZB, and Reed S. Drugs targeting parasite lysosomes (Chapter 9). In Current Pharmaceutical Design. 14:889-900;2008.
• Mottram JC and Sajid M. Trichomonad and Giardia Cysteine Endopeptidases (Chapter 365). In. Handbook of Proteolytic Enzymes. Edit. Barrett AJ, Rawlings ND and Woessner JF. 2004. Academic Press.
• Dalton J, Caffrey CR, Sajid M, Stack C, Donelly S, Loukas A, Don T, McKerrow JH, Halton DW, Brindley PJ. Protease in Trematode Biology (Part III), in. Parasitic Flatworms: Molecular Biology, Biochemistry, Immunology and Physiology. Edit. Maule AG. 2006. CAB International.
• Isaac RE, Schoofs L, Williams TA, Veelaert D, Sajid M and Coates D. The co-localisation of angiotensin I-converting enzyme; Towards a role for angiotensin-converting enzyme. in Trends in Comparative Endocrinology and Neurobiology. Annals of the New York Academy of Sciences. 1997.