Screening for New Peptide Substrates For the Development of Albumin Binding Anticancer Pro-Drugs That Are Cleaved By Prostate-Specific Antigen (PSA) to Improve The Anti Tumor Efficacy

Bakheet E.M et al., Biochemistry and Biophysics Reports (2020) - PMID: 33718631

Product(s) used in this publication:  Specialty Peptides


Several attempts have been made over the past decade to explore the concept of prodrug strategies that exploit PSA as a molecular target for the release of anticancer drugs in prostate tumors using various prostate specific antigen (PSA)-cleavable peptide linkers, but the desired antitumor and antimetastatic efficacy has not yet been fully achieved. We set out to look for new PSA-cleavable peptide substrates that could be cleaved more rapidly and efficiently than the previously used peptides. To look for the most susceptible PSA-cleavable peptide substrates, we used the so-called spot technology. With the following general formula, we designed 25 different fluorogenic heptapeptides; Cellulose-P5-P4-P3-P2-P1-P1'-P2' (Fluorophore). The increase of the fluorescence in the supernatant of the reaction mixture was monitored using a 96-well fluorometric plate reader with excitation of λex 485 nm and λem 535 nm. Three sequences showed a high fluorogenic liberation after incubation with PSA, i.e., Arg-Arg-Leu-His-Tyr-Ser-Leu (7), Arg-Arg-Leu-Asn-Tyr-Ser-Leu (8) and Arg-Ser-Ser-Tyr-Arg-Ser-Leu (23). Future incorporation of these optimized substrates in the PSA-cleavable prodrug formulations could further optimize the cleavage pattern and so the release characteristics of these prodrugs to rapidly and efficiently liberate the free cytotoxic agents inside the tumor tissues.

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