Research

The rapid advancement of combinatorial chemistry offers chemists unprecedented power to quickly and efficiently generate large number of diverse molecules for screening desired properties. We are actively engaged in using combinatorial chemistry to generate and optimize lead compounds in a structure-based drug design cycle. One specific example is to design ultra-high affinity inhibitors for the receptor recognition process of cholera toxin (CT) and E. coli heat-labile enterotoxin (LT). CT and LT belong to a so-called AB5 family of bacterial toxins. Their symmetrical pentameric B subunits are responsible for cell surface receptor recognition, a critical step for the toxins' invasion into host cells. Based on the the high-resolution crystal structures of either CT or LT, we are trying to design and synthesize simple sugar molecules which can have affinities similar to the toxins' nature glycolipid head group. Then, by linking up to five copies of these small inhibitors together, we can gain several orders of magnitude further in affinity. This strategy will allow us to develop effective therapeutics against both CT and LT.

Selected Publications

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.

Zhang Z, Fan E (2005) Solid-phase and solution-phase syntheses of oligomeric guanidines bearing peptide side chains. J Org Chem 70, 8801-8810.

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.

Mitchell DD, Pickens JC, Korotkov K, Fan E, Hol WG (2004) 3,5-Substituted phenyl galactosides as leads in designing effective cholera toxin antagonists; synthesis and crystallographic studies. Bioorg Med Chem 12, 907-920.

Ogata Y, Scampavia L, Carter TL, Fan E, Turecek F (2004) Automated affinity chromatography measurements of compound mixtures using a lab-on-valve apparatus coupled to electrospray ionization mass spectrometry. Anal Biochem 331, 161-168.

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.

Zhang Z, Pickens JC, Hol WG, Fan E (2004) Solution- and solid-phase syntheses of guanidine-bridged, water-soluble linkers for multivalent ligand design. Org Lett 6, 1377-1380.

Choe J, Moyersoen J, Roach C, Carter TL, Fan E, Michels PA, Hol WG (2003) Analysis of the sequence motifs responsible for the interactions of peroxins 14 and 5, which are involved in glycosome biogenesis in Trypanosoma brucei. Biochemistry 42, 10915-10922.

Merritt EA, Zhang Z, Pickens JC, Ahn M, Hol WG, Fan E (2002) Characterization and crystal structure of a high-affinity pentavalent receptor-binding inhibitor for cholera toxin and E. coli heat-labile enterotoxin. J Am Chem Soc 124, 8818-8824.

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.

Fan E, Merritt EA, Zhang Z, Pickens JC, Roach C, Ahn M, Hol WG (2001) Exploration of the GM1 receptor-binding site of heat-labile enterotoxin and cholera toxin by phenyl-ring-containing galactose derivatives. Acta Crystallogr D Biol Crystallogr 57, 201-212.

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.