Metallo-aminopeptidase Inhibitors

Overview

Journal Biochimie

Specialty Biochemistry

Date 2010 May 12

PMID 20457213

Citations 41

Authors

Artur Mucha

Marcin Drag

John P Dalton

Pawel Kafarski

Affiliations

Soon will be listed here.

Abstract

Aminopeptidases are enzymes that selectively hydrolyze an amino acid residue from the N-terminus of proteins and peptides. They are important for the proper functioning of prokaryotic and eukaryotic cells, but very often are central players in the devastating human diseases like cancer, malaria and diabetes. The largest aminopeptidase group include enzymes containing metal ion(s) in their active centers, which often determines the type of inhibitors that are the most suitable for them. Effective ligands mostly bind in a non-covalent mode by forming complexes with the metal ion(s). Here, we present several approaches for the design of inhibitors for metallo-aminopeptidases. The optimized structures should be considered as potential leads in the drug discovery process against endogenous and infectious diseases.

Citing Articles

Synthesis, biological and pharmacokinetic characterization of a novel leucine ureido derivative as a multi-target anticancer agent.

Shi F, Xu Q, Zhang Y, Cao J, Liu C, Liu A RSC Adv. 2025; 15(6):4348-4355.

PMID: 39931415 PMC: 11808297. DOI: 10.1039/d4ra03200d.

Destined for destruction: The role of methionine aminopeptidases and plant cysteine oxidases in N-degron formation.

Fuentes-Terron A, Latter R, Madden S, Manrique-Gil I, Estrada J, Arteaga N Plant Physiol. 2025; 197(1).

PMID: 39875105 PMC: 11773813. DOI: 10.1093/plphys/kiae667.

Naturally based pyrazoline derivatives as aminopeptidase N, VEGFR2 and MMP9 inhibitors: design, synthesis and molecular modeling.

Batran R, Ahmed E, Awad H, Abdel Latif N RSC Adv. 2024; 14(31):22434-22448.

PMID: 39010911 PMC: 11248911. DOI: 10.1039/d4ra01801j.

Quantifying and Controlling the Proteolytic Degradation of Cell Adhesion Peptides.

Rozans S, Moghaddam A, Wu Y, Atanasoff K, Nino L, Dunne K ACS Biomater Sci Eng. 2024; 10(8):4916-4926.

PMID: 38968389 PMC: 11322908. DOI: 10.1021/acsbiomaterials.4c00736.

Drug targeting of aminopeptidases: importance of deploying a right metal cofactor.

Bhat S Biophys Rev. 2024; 16(2):249-256.

PMID: 38737204 PMC: 11078913. DOI: 10.1007/s12551-024-01192-8.

References

Lowther W, Matthews B . Metalloaminopeptidases: common functional themes in disparate structural surroundings. Chem Rev. 2002; 102(12):4581-608. DOI: 10.1021/cr0101757. View

Kazeto H, Nomura S, Ito N, Ito T, Watanabe Y, Kajiyama H . Expression of adipocyte-derived leucine aminopeptidase in endometrial cancer. Association with tumor grade and CA-125. Tumour Biol. 2003; 24(4):203-8. DOI: 10.1159/000074431. View

Wang W, Chai S, Huang M, He H, Hurley T, Ye Q . Discovery of inhibitors of Escherichia coli methionine aminopeptidase with the Fe(II)-form selectivity and antibacterial activity. J Med Chem. 2008; 51(19):6110-20. PMC: 2737180. DOI: 10.1021/jm8005788. View

Michalska K, Brzezinski K, Jaskolski M . Crystal structure of isoaspartyl aminopeptidase in complex with L-aspartate. J Biol Chem. 2005; 280(31):28484-91. DOI: 10.1074/jbc.M504501200. View

Cunningham E, Drag M, Kafarski P, Bell A . Chemical target validation studies of aminopeptidase in malaria parasites using alpha-aminoalkylphosphonate and phosphonopeptide inhibitors. Antimicrob Agents Chemother. 2008; 52(9):3221-8. PMC: 2533478. DOI: 10.1128/AAC.01327-07. View

Chen H, Roques B, Fournie-Zaluski M . Design of the first highly potent and selective aminopeptidase N (EC 3.4.11.2) inhibitor. Bioorg Med Chem Lett. 1999; 9(11):1511-6. PMC: 7172755. View

Kaur R, Agrawal N, Bhatnagar R . Purification and characterization of aminopeptidase N from Spodoptera litura expressed in Sf21 insect cells. Protein Expr Purif. 2007; 54(2):267-74. DOI: 10.1016/j.pep.2007.03.003. View

McGowan S, Porter C, Lowther J, Stack C, Golding S, Skinner-Adams T . Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc Natl Acad Sci U S A. 2009; 106(8):2537-42. PMC: 2636733. DOI: 10.1073/pnas.0807398106. View

Nagai M, Kojima F, Naganawa H, Hamada M, Aoyagi T, Takeuchi T . Phebestin, a new inhibitor of aminopeptidase N, produced by Streptomyces sp. MJ716-m3. J Antibiot (Tokyo). 1997; 50(1):82-4. DOI: 10.7164/antibiotics.50.82. View

10.

Drag M, Pawelczak M, Kafarski P . Stereoselective synthesis of 1-aminoalkanephosphonic acids with two chiral centers and their activity towards leucine aminopeptidase. Chirality. 2003; 15 Suppl:S104-7. DOI: 10.1002/chir.10261. View

11.

Skinner-Adams T, Lowther J, Teuscher F, Stack C, Grembecka J, Mucha A . Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds. J Med Chem. 2007; 50(24):6024-31. DOI: 10.1021/jm070733v. View

12.

Isaac R, Bland N, Shirras A . Neuropeptidases and the metabolic inactivation of insect neuropeptides. Gen Comp Endocrinol. 2009; 162(1):8-17. DOI: 10.1016/j.ygcen.2008.12.011. View

13.

Baker J, Wilkes S, BAYLISS M, PRESCOTT J . Hydroxamates and aliphatic boronic acids: marker inhibitors for aminopeptidase. Biochemistry. 1983; 22(9):2098-103. DOI: 10.1021/bi00278a009. View

14.

Fulda S, Scaffidi C, Susin S, Krammer P, Kroemer G, Peter M . Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem. 1998; 273(51):33942-8. DOI: 10.1074/jbc.273.51.33942. View

15.

Drag M, Bogyo M, Ellman J, Salvesen G . Aminopeptidase fingerprints, an integrated approach for identification of good substrates and optimal inhibitors. J Biol Chem. 2009; 285(5):3310-8. PMC: 2823418. DOI: 10.1074/jbc.M109.060418. View

16.

Dasgupta B, Yi Y, Hegedus B, Weber J, Gutmann D . Cerebrospinal fluid proteomic analysis reveals dysregulation of methionine aminopeptidase-2 expression in human and mouse neurofibromatosis 1-associated glioma. Cancer Res. 2005; 65(21):9843-50. DOI: 10.1158/0008-5472.CAN-05-1842. View

17.

Cappiello M, Alterio V, Amodeo P, Del Corso A, Scaloni A, Pedone C . Metal ion substitution in the catalytic site greatly affects the binding of sulfhydryl-containing compounds to leucyl aminopeptidase. Biochemistry. 2006; 45(10):3226-34. DOI: 10.1021/bi052069v. View

18.

Lejczak B, Kafarski P, Zygmunt J . Inhibition of aminopeptidases by aminophosphonates. Biochemistry. 1989; 28(8):3549-55. DOI: 10.1021/bi00434a060. View

19.

Ataie N, Hoang Q, Zahniser M, Tu Y, Milne A, Petsko G . Zinc coordination geometry and ligand binding affinity: the structural and kinetic analysis of the second-shell serine 228 residue and the methionine 180 residue of the aminopeptidase from Vibrio proteolyticus. Biochemistry. 2008; 47(29):7673-83. PMC: 3119262. DOI: 10.1021/bi702188e. View

20.

Deejing S, Yoshimune K, Lumyong S, Moriguchi M . Purification and characterization of hyperthermotolerant leucine aminopeptidase from Geobacillus thermoleovorans 47b. J Ind Microbiol Biotechnol. 2005; 32(7):269-76. DOI: 10.1007/s10295-005-0236-z. View