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Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of human aminopeptidase N

F H Hausheer1, A R Parker, P N Petluru

  • 1BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Suite 400, San Antonio, TX 78229, USA. fred.hausheer@bnpi.com

Cancer Chemotherapy and Pharmacology
|May 5, 2010
PubMed
Abstract

Insights

BNP7787, a cisplatin nephroprotection agent, may work by inhibiting aminopeptidase N (APN) with specific mesna-disulfide heteroconjugates. This inhibition, linked to glycinate or anionic groups, may prevent cisplatin-induced kidney damage.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • Previous research identified gamma-glutamyl transpeptidase (GGT) in BNP7787-mediated cisplatin nephroprotection.
  • A proposed multi-enzyme pathway (GGT, aminopeptidase N [APN], cysteine-conjugate-β-lyase [CCBL]) converts xenobiotic-glutathione conjugates to nephrotoxic metabolites.

Purpose of the Study:

  • To investigate the modulation of APN activity by BNP7787-derived mesna-disulfide heteroconjugates.
  • To understand the role of APN in the context of the proposed xenobiotic metabolism pathway.

Main Methods:

  • Utilized a fluorimetric assay to assess the impact of BNP7787, its derivatives, and mesna on human APN activity in vitro.
  • Examined both initial reaction velocity and overall enzyme progress curves.

Main Results:

  • BNP7787 and mesna-cysteinyl-glutamate did not inhibit human APN.
  • Specific heteroconjugates (mesna-cysteine, mesna-glutathione, mesna-cysteinyl-glycine) and high mesna concentrations inhibited APN.
  • Allosteric inhibition was observed with certain heteroconjugates, dependent on mesna and peptide functionalities.
  • In situ-generated mesna-cisplatin conjugates were not substrates for APN.

Conclusions:

  • BNP7787-mediated nephroprotection may involve APN inhibition by specific heteroconjugates, correlated with glycinate or anionic groups.
  • Two proposed mechanisms for BNP7787 nephroprotection involve the GGT, APN, and CCBL pathway acting synergistically to mitigate cisplatin renal toxicity.

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