Recent developments in the synthesis and applications of phosphinic peptide analogs

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 9; pp. 1031 - 1042
• Main Authors: Talma, Michał, Maślanka, Marta, Mucha, Artur
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2019
• Subjects: Bacteria - enzymology; Biological activity; Enzyme inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Humans; Matrix Metalloproteinases - chemistry; Matrix Metalloproteinases - metabolism; Metals - chemistry; Peptide analogs; Peptide Synthases - antagonists & inhibitors; Peptide Synthases - metabolism; Peptides - chemical synthesis; Peptides - chemistry; Peptides - metabolism; Phosphinic acids; Phosphinic Acids - chemistry; Prostate-Specific Antigen - chemistry; Prostate-Specific Antigen - metabolism; Phosphinic acids; Enzyme inhibitors; Peptide analogs; Biological activity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.02.034

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•Phosphinic peptides are transition state inhibitors of Zn-proteases and ligases.•Binding to the active sites involves metal complexation and backbone complementarity.•Activity and physicochemical properties of phosphinates can be conveniently adjusted.•Phosphinic acids provide structural cores for affinity-based probes and radioligands.
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.