Department of Biochemistry Box 357350 University of Washington Seattle, WA 98195
 



 
 
 

    
Christophe Verlinde      
    Associate Professor of Biochemistry

    MS 1981 University of Leuven, Belgium
    PhD 1988 University of Leuven, Belgium

    206.543.8865 V
    206.685.7002 F
    verlinde@u.washington.edu

 

Research

Research in the Verlinde group focuses on structure-based drug design, the discovery and design of new therapeutic agents based on the atomic three-dimensional structures of biochemical targets. We design inhibitors of various proteins from pathogens whose structure has been determined in the groups of our colgrouporators Dr. Hol and Dr. Merritt.

A remarkable success has been the design of a selective inhibitor of glyceraldehyde-3-phosphate dehydrogenase from trypanosomes, synthesized by our colgrouporator Dr. Gelb, which kills the organisms in culture while leaving mammalian cells unharmed. Five orders of magnitude in affinity were gained by the design methods. Other efforts focus at the design of three different types of agents that could inhibit the devastating action of cholera toxin: B-subunit antagonists: compounds that block competitively the binding of the toxin's B-subunits to GM1 gangliosides of the target cell, thereby preventing the entry of the toxin into the cell; (2) A-subunit antagonists: competitive and non-competitive inhibitors of the toxin's ADP-ribosylating A subunit, thereby blocking directly the irreversible modification of the stimulatory G-protein, or indirectly the conformational activation of the A subunit; (3) AB5 assembly blockers: molecules that prevent proper assembly of these AB5 toxins, thereby producing incomplete and incompetent heteromers. A pipeline of several new protein targets from protozoal parasites is avaigrouple for new drug design projects, and more will become avaigrouple through our participation in the Structural Genomics of Protozoal Parasites (SGPP) project.

We also work on developing new methodologies for structure-based drug design. Recently, we created a new docking program SAS, based on stochastic approximation with smoothing, for predicting the binding mode of flexible drug-like molecules to proteins. This method outperforms dramatically traditional docking methods such as simulated annealing.


Selected Publications

Cho HD, Verlinde CL & Weiner AM (2005). Archaeal CCA-adding enzymes: central role of a highly conserved beta-turn motif in RNA polymerization without translocation. J Biol Chem 280, 9555-9566.

Eastman RT, White J, Hucke O, Bauer K, Yokoyama K, Nallan L, Chakrabarti D, Verlinde CL, Gelb MH, Rathod PK & Van Voorhis WC (2005). Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum. J Biol Chem 280, 13554-13559.

Hucke O, Gelb MH, Verlinde CL & Buckner FS (2005). The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease. J Med Chem 48, 5415-5418.

Liu J, Zhang Z, Tan X, Hol WG, Verlinde CL & Fan E (2005). Protein heterodimerization through ligand-bridged multivalent pre-organization: enhancing ligand binding toward both protein targets. J Am Chem Soc 127, 2044-2045.

Robien MA, Bosch J, Buckner FS, Van Voorhis WC, Worthey EA, Myler P, Mehlin C, Boni EE, Kalyuzhniy O, Anderson L, Lauricella A, Gulde S, Luft JR, Detitta G, Caruthers JM, Hodgson KO, Soltis M, Zucker F, Verlinde CL, Merritt EA, Schoenfeld LW & Hol WG (2005). Crystal structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum at 2.25 A resolution reveals intriguing extra electron density in the active site. Proteins.

Shao B, Belaaouaj A, Verlinde CL, Fu X & Heinecke JW (2005). Methionine sulfoxide and proteolytic cleavage contribute to the inactivation of cathepsin G by hypochlorous acid: an oxidative mechanism for regulation of serine proteinases by myeloperoxidase. J Biol Chem 280, 29311-29321.

Tai G, Farin F, Rieder MJ, Dreisbach AW, Veenstra DL, Verlinde CL & Rettie AE (2005). In-vitro and in-vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose. Pharmacogenet Genomics 15, 475-481.

Fan E, O'Neal CJ, Mitchell DD, Robien MA, Zhang Z, Pickens JC, Tan XJ, Korotkov K, Roach C, Krumm B, Verlinde CL, Merritt EA & Hol WG (2004). Structural biology and structure-based inhibitor design of cholera toxin and heat-labile enterotoxin. Int J Med Microbiol 294, 217-223.

Pickens JC, Mitchell DD, Liu J, Tan X, Zhang Z, Verlinde CL, Hol WG & Fan E (2004). Nonspanning bivalent ligands as improved surface receptor binding inhibitors of the cholera toxin B pentamer. Chem Biol 11, 1205-1215.

Zhang Z, Liu J, Verlinde CL, Hol WG & Fan E (2004). Large cyclic peptides as cores of multivalent ligands: application to inhibitors of receptor binding by cholera toxin. J Org Chem 69, 7737-7740.

Pickens JC, Merritt EA, Ahn M, Verlinde CL, Hol WG & Fan E (2002). Anchor-based design of improved cholera toxin and E. coli heat-labile enterotoxin receptor binding antagonists that display multiple binding modes. Chem Biol 9, 215-224.

Zhang Z, Merritt EA, Ahn M, Roach C, Hou Z, Verlinde CL, Hol WG & Fan E (2002). Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin. J Am Chem Soc 124, 12991-12998.

Bressi JC, Verlinde CL, Aronov AM, Shaw ML, Shin SS, Nguyen LN, Suresh S, Buckner FS, Van Voorhis WC, Kuntz ID, Hol WG & Gelb MH (2001). Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design. J Med Chem 44, 2080-2093.

Suresh S, Bressi JC, Kennedy KJ, Verlinde CL, Gelb MH & Hol WG (2001). Conformational changes in Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase induced by designed inhibitors. J Mol Biol 309, 423-435.

Verlinde CL, Hannaert V, Blonski C, Willson M, Perie JJ, Fothergill-Gilmore LA, Opperdoes FR, Gelb MH, Hol WG & Michels PA (2001). Glycolysis as a target for the design of new anti-trypanosome drugs. Drug Resist Updat 4, 50-65.

Bressi JC, Choe J, Hough MT, Buckner FS, Van Voorhis WC, Verlinde CL, Hol WG & Gelb MH (2000). Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: elucidation of a novel binding mode for a 2-amino-N(6)-substituted adenosine. J Med Chem 43, 4135-4150.

Cideciyan AV, Haeseleer F, Fariss RN, Aleman TS, Jang GF, Verlinde CL, Marmor MF, Jacobson SG & Palczewski K (2000). Rod and cone visual cycle consequences of a null mutation in the 11-cis-retinol dehydrogenase gene in man. Vis Neurosci 17, 667-678.

Fan E, Merritt EA, Verlinde CL & Hol WG (2000). AB(5) toxins: structures and inhibitor design. Curr Opin Struct Biol 10, 680-686.

Minke WE, Pickens J, Merritt EA, Fan E, Verlinde CL & Hol WG (2000). Structure of m-carboxyphenyl-alpha-D-galactopyranoside complexed to heat-labile enterotoxin at 1.3 A resolution: surprising variations in ligand-binding modes. Acta Crystallogr D Biol Crystallogr 56 (Pt 7), 795-804.

Sokal I, Li N, Verlinde CL, Haeseleer F, Baehr W & Palczewski K (2000). Ca(2+)-binding proteins in the retina: from discovery to etiology of human disease(1). Biochim Biophys Acta 1498, 233-251.