Design of a New Peptide Substrate Probe of the Putative Biomarker Legumain with Potential Application in Prostate Cancer Diagnosis Ex Vivo

Sunil Mathur, Agnes Turnbull, Iolia Akaev, Craig Stevens, Neerja Agrawal, Mridula Chopra, David Mincher (Lead / Corresponding author)

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Abstract

The lysosomal endoprotease legumain (asparaginyl endoprotease) has been proposed as a putative biomarker in prostate tumours, in which the enzyme is markedly overexpressed. Overexpression, coupled with highly selective specificity for cleavage of substrates at the C-terminus of asparagine (Asn) residues, make legumain an attractive biochemical target for potential diagnosis, prognosis and treatment. We report the design, synthesis, characterisation and preliminary evaluation of a new rhodamine-B (Rho-B)-labelled legumain peptide substrate probe 5 [Rho-Pro-Ala-Asn-PEG-AQ(4-OH)] and its selective targeting to lysosomes in PC3 prostate cancer cells. Probe 5 was efficiently activated by recombinant human legumain to afford the high quantum yield reporter fluorophore tripeptide 4b (Rho-Pro-Ala-Asn-OH) with concomitant release of intense fluorescence. Furthermore, probe 5 was activated upon incubation with homogenates derived from fresh-frozen tissue material of prostatectomy specimens. Probe 5 represents a new viable biochemical tool for probing the activity of legumain with the potential to be used in ex vivo diagnostics in the cancer pathology laboratory.

Original languageEnglish
Number of pages16
JournalInternational Journal of Peptide Research and Therapeutics
Early online date17 Dec 2019
DOIs
Publication statusE-pub ahead of print - 17 Dec 2019

Keywords

  • Biomarker
  • Diagnosis
  • Legumain
  • Prostate cancer
  • Synthesis

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