3,5-Substituted phenyl galactosides as leads in designing effective cholera toxin antagonists: Synthesis and crystallographic studies

Daniel D. Mitchell, Jason C. Pickens, Konstantin Korotkov, Erkang Fan, Wim G.J. Hol

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

With the aim of developing high-affinity mono and multivalent antagonists of cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) we are using the galactose portion of the natural receptor ganglioside GM1 as an anchoring fragment in structure-based inhibitor design efforts. In order to establish a better structure-activity relationship for guiding these studies, we designed and prepared a small focused library of twenty 3,5-substituted phenylgalactosides based on two previous leads. The compounds were tested for their ability to block CTB5 binding to immobilized ganglioside receptor and compared to the two previous leads. The crystal structures of the most promising compounds bound to either CTB5 or LTB5 were then determined in order to understand the basis for affinity differences. The most potent new compound yielded a six-fold improvement over our benchmark lead m-nitrophenyl-α-D-galactopyranoside (MNPG), and a two-fold improvement in IC50 over a newer MNPG derivative. These results support the notion that the m-nitrophenyl moiety of MNPG and its derivatives is an important element to retain in future optimization efforts. Additionally, a consensus binding-pocket for the alkylmorpholine or piperazine moiety present in all of the designed antagonists was established as an important area of the GM1 binding site to target in future work.

Original languageEnglish
Pages (from-to)907-920
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number5
DOIs
StatePublished - Mar 1 2004

Bibliographical note

Funding Information:
This work was supported in part by the National Institutes of Health (grant AI44954 to EF and grant AI34501 to WGJH). We also would like to thank Stewart Turley for assistance with crystallographic data collection and Drs. Ethan Merritt and Christophe Verlinde for stimulating discussions and advice. We gratefully acknowledge the staff of beamline 8.2.2 at the Advanced Light Source, and the staff at the SBC beamline 19ID for assistance in data collection. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source were supported by the US Department of Energy, Office of Biological and Environmental Research, under contract number W-31-109-ENG-38. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, Materials Sciences Division, of the US Department of Energy under Contract No. DE-AC03-76SF00098 at Lawrence Berkeley National Laboratory.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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