Design and synthesis of an Fmoc-SPPS-compatible amino acid building block mimicking the transition state of phosphohistidine phosphatase

J Org Chem. 2012 Feb 17;77(4):2047-52. doi: 10.1021/jo2025702. Epub 2012 Feb 7.

Abstract

The synthesis of a sulfonamide-based transition-state (TS) analogue of enzymatic phosphohistidine dephosphorylation as an amino acid building block is presented, together with the proof-of-concept of its incorporation into peptides. Key features include final global acidolytic protective group removal as well as full compatibility with standard Fmoc solid-phase peptide synthesis (SPPS). The peptides are designed as inhibitors of phosphohistidine phosphatase and as a pull-down probe for identification of phosphohistidine phosphatases, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Fluorenes / chemistry
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Mimicry
  • Molecular Sequence Data
  • Molecular Structure
  • Peptides / chemical synthesis*
  • Peptides / metabolism
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphoric Monoester Hydrolases / metabolism
  • Solid-Phase Synthesis Techniques
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / metabolism

Substances

  • Amino Acids
  • Enzyme Inhibitors
  • Fluorenes
  • N(alpha)-fluorenylmethyloxycarbonylamino acids
  • Peptides
  • Sulfonamides
  • PHPT1 protein, human
  • Phosphoric Monoester Hydrolases