Recent developments in the synthesis and applications of phosphinic peptide analogs

Bioorg Med Chem Lett. 2019 May 1;29(9):1031-1042. doi: 10.1016/j.bmcl.2019.02.034. Epub 2019 Feb 28.

Abstract

Synthetic pseudopeptides that fit well with the active site architecture allow the most effective binding to enzymes, similar to native substrates in high-energy transition states. Phosphinic acid peptide analogs that comprise the tetrahedral phosphorus moiety introduced to replace an internal amide bond exert such an isosteric or isoelectronic resemblance, combined with providing other advantageous features, for example, metal complexing properties. Accordingly, they are capable of inhibiting metal-dependent enzymes involved in biological functions in eukaryotic and prokaryotic cells. These enzymes are associated with notorious human diseases, such as cancer, e.g., matrix metalloproteinases, or are etiological factors of protozoal and bacterial infections, e.g., metalloaminopeptidases. The affinity and selectivity of these compounds can be conveniently adjusted, either by structural modification of dedicated side chains or by backbone elongation to enhance specific interactions with the corresponding binding pockets. Recent approaches to the synthesis of these compounds are illustrated by examples of the preparation of rationally designed structures of inhibitors of particular enzymes. Activity against appealing enzymatic targets is presented, along with the molecular mechanisms of action and therapeutic implications. Innovative aspects of phosphinic peptide application, e.g., as activity-based probes, and ligands of complexes of radioisotopes for nuclear medicine are also outlined.

Keywords: Biological activity; Enzyme inhibitors; Peptide analogs; Phosphinic acids.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bacteria / enzymology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Humans
  • Matrix Metalloproteinases / chemistry
  • Matrix Metalloproteinases / metabolism
  • Metals / chemistry
  • Peptide Synthases / antagonists & inhibitors
  • Peptide Synthases / metabolism
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / metabolism
  • Phosphinic Acids / chemistry*
  • Prostate-Specific Antigen / chemistry
  • Prostate-Specific Antigen / metabolism

Substances

  • Enzyme Inhibitors
  • Metals
  • Peptides
  • Phosphinic Acids
  • Prostate-Specific Antigen
  • Matrix Metalloproteinases
  • Peptide Synthases
  • tubulin polyglutamylase