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CPP-Ala-Ala-Tyr-PABA inhibitor analogs with improved selectivity for neurolysin or thimet oligopeptidase
- Source :
- Biochemical and biophysical research communications. 522(2)
- Publication Year :
- 2019
-
Abstract
- Thimet oligopeptidase (TOP, EC 3.4.24.15) and neurolysin (NEL, EC 3.4.24.16) are closely related zinc-dependent metalo-oligopeptidases, which take part in the metabolism of oligopeptides (from 5 to 17 amino acid residues) inside and outside cells. Both peptidases are ubiquitously distributed in tissues. TOP is one of the main intracellular peptide-processing enzymes being important for the antigen selection in the MHC Class I presentation route, while NEL function has been more associated with the extracellular degradation of neurotensin. Despite efforts being made to develop specific inhibitors for these peptidases, the most used are: CPP-Ala-Ala-Tyr-PABA, described by Orlowski et al. in 1988, and CPP-Ala-Aib-Tyr-PABA (JA-2) that is an analog more resistant to proteolysis, which development was made by Shrimpton et al. in 2000. In the present work, we describe other analogs of these compounds but, with better discriminatory capacity to inhibit specifically NEL or TOP. The modifications introduced in these new analogs were based on a key difference existent in the extended binding sites of NEL and TOP: the negatively charged Glu469 residue of TOP corresponds to the positively charged Arg470 residue of NEL. These residues are in position to interact with the residue at the P1′ and/or P2′ of their substrates (mimicked by the Ala-Ala/P1′-P2′ residues of the CPP-Ala-Ala-Tyr-PABA). Therefore, exploring this single difference, the following compounds were synthesized: CPP-Asp-Ala-Tyr-PABA, CPP-Arg-Ala-Tyr-PABA, CPP-Ala-Asp-Tyr-PABA, CPP-Ala-Arg-Tyr-PABA. Confirming the predictions, the replacement of each non-charged residue of the internal portion Ala-Ala by a charged residue Asp or Arg resulted in compounds with higher selectivity for NEL or TOP, especially due to the electrostatic attraction or repulsion by the NEL Arg470 or TOP Glu469 residue. The CPP-Asp-Ala-Tyr-PABA and CPP-Ala-Asp-Tyr-PABA presented higher affinities for NEL, and, the CFP-Ala-Arg-Tyr-PABA showed higher affinity for TOP.
- Subjects :
- 0301 basic medicine
Stereochemistry
Proteolysis
Biophysics
Biochemistry
Substrate Specificity
03 medical and health sciences
Residue (chemistry)
0302 clinical medicine
MHC class I
Extracellular
medicine
Binding site
Molecular Biology
chemistry.chemical_classification
Oligopeptide
Thimet oligopeptidase
biology
medicine.diagnostic_test
Metalloendopeptidases
Cell Biology
Kinetics
030104 developmental biology
Enzyme
chemistry
030220 oncology & carcinogenesis
Mutation
biology.protein
Oligopeptides
Subjects
Details
- ISSN :
- 10902104
- Volume :
- 522
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Biochemical and biophysical research communications
- Accession number :
- edsair.doi.dedup.....2bfeb2fabbb0f248080128178e9709e7