Phosphonopeptides containing free phosphonic groups: recent advances

Abstract

Phosphonopeptides are mimetics of peptides in which phosphonic acid or related (phosphinic, phosphonous etc.) group replaces either carboxylic acid group present at C-terminus, is located in the peptidyl side chain, or phosphonamidate or phosphinic acid mimics peptide bond. Acting as inhibitors of key enzymes related to variable pathological states they display interesting and useful physiologic activities with potential applications in medicine and agriculture. Since the synthesis and biological properties of peptides containing C-terminal diaryl phosphonates and those with phosphonic fragment replacing peptide bond were comprehensively reviewed, this review concentrate on peptides holding free, unsubstituted phosphonic acid moiety. There are two groups of such mimetics: (i) peptides in which aminophosphonic acid is located at C-terminus of the peptide chain with most of them (including antibiotics isolated from bacteria and fungi) exhibiting antimicrobial activity; (ii) non-hydrolysable analogues of phosphonoamino acids, which are useful tools to study physiologic effects of phosphorylations.

Fig. 1. Representative examples of structurally different phosphonopeptides.

Fig. 2. Mechanism of action of alafosfalin and bialaphos.

Fig. 3. Naturally occurring phosphonopeptide antibiotics.

Fig. 4. Structurally variable peptides containing C-terminal aminophosphonic acids.

Fig. 5. Synthesis of dehydrophos.

Fig. 6. Synthesis of phosphonopeptides by Mannich-like approach.

Fig. 7. Thiourea containing phosphonopeptides.

Fig. 8. Synthesis of peptides containing 1-hydroxy-2-aminoalkylphosphponates.

Fig. 9. Mode of binding of peptide 28 by cathepsin K.

Fig. 10. Phosphonopeptides designed as phases for chromatography.

Fig. 11. Synthesis of phosphonopeptides via 5-amino-1,3-oxazol-4-ylphosphonates.

Fig. 12. Functionalization of phosphonodehydropeptide.

Fig. 13. Mimetics of phosphothreonine and its peptides.

Fig. 14. Representative synthetic route to mimetic of phosphothreonine.

Fig. 15. Peptides containing non-hydrolysable mimetics of phosphotyrosine designed to bind 14-3-3-proteins.

Fig. 16. Prodrug design for transportation of affinity probe through cell membranes.

Fig. 17. Peptides containing mimetic of pyrophosphate-substituted serine.

Fig. 18. pH-responsive polymers of phosphoserine mimetics.

Fig. 19. Analogues of phosphotyrosine designed to study Src SH2 homology domains and tyrosine phosphatases.

Fig. 20. Photoactive analogue of phosphotyrosine and its peptides.

Fig. 21. Peptides containing non-hydrolysable analogue of phosphotyrosine.

Fig. 22. Modified Stichodactyla helianthus peptide as potential agent against multiple sclerosis.

Fig. 23. Non-hydrolysable analogues of phosphohistidine.

Fig. 24. Representative antigens containing mimetics of phosphohistidine.

Fig. 25. Synthesis of analogues of phosphohistidine via click reaction.

Fig. 26. Synthesis of phosphohistidine analogue 68.

Fig. 27. Peptide containing analogue of phosphohistidine 76, which acts as mimic of phosphotyrosine.

Fig. 28. CheY protein functionalized with phosphorus fragments.

Fig. 29. Bisphosphonates as drug carriers.

Fig. 30. Polymeric peptides of phosphonate holding amino acids.

Fig. 31. Naturally occurring phosphonate peptidomimetics.

Paweł Kafarski