Pseudoirreversible inhibition of prostate-specific membrane antigen by phosphoramidate peptidomimetics

Biochemistry. 2008 Dec 2;47(48):12658-60. doi: 10.1021/bi801883v.


The mode of inhibition for phosphoramidate peptidomimetic inhibitors of prostate-specific membrane antigen was determined by inhibition reversibility experiments. The results revealed that these inhibitors can be classified into three types: pseudoirreversible (compounds 1-3), moderately reversible (compounds 4-9), and rapidly reversible inhibitors (compounds 10 and 11). Representative compounds from each class were further evaluated for their ability to induce cellular internalization of PSMA. Results from these experiments revealed that the pseudoirreversible inhibitor 1 induced the greatest PSMA internalization. The discovery of pseudoirreversible PSMA inhibitors is expected to provide a new avenue of investigation and therapeutic applications for prostate cancer and neurological disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amides / chemistry*
  • Animals
  • Antigens, Surface / metabolism
  • Biomimetic Materials / chemistry*
  • Biomimetic Materials / pharmacology*
  • Cell Line
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / metabolism
  • Humans
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Phosphoric Acids / chemistry*
  • Protein Transport / drug effects


  • Amides
  • Antigens, Surface
  • Enzyme Inhibitors
  • Peptides
  • Phosphoric Acids
  • phosphoramidic acid
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II