Protease-mediated arsenic prodrug strategy in cancer and infectious diseases: A hypothesis for targeted activation

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Abstract

A strategy for the selective in vivo activation of prodrugs by proteases is presented. The approach is based on the design of polythiol peptides able to neutralize the toxicity of As(III) through chelation, and contemporarily to be recognized as substrates of a disease-linked specific protease. Enzyme digestion implies conversion of such polythiol peptides into monothiol fragments with irreversible loss of the ability to chelate the metalloid, thus triggering the release in its free and pharmacologically effective form. The proteases whose activity appears dramatically up-regulated in various pathologies, ranging from cancer to infectious diseases, can be conveniently employed as prodrug activators in the disease microenvironment. The design of the representative peptide shown here has been assisted by molecular modeling in order to fulfill the dual characteristic to be an efficient As(III) chelator and simultaneously a substrate of the matrix metalloproteinase-9 (MMP-9) whose activity results dramatically increased at the surface of cells affected by several pathologies.

Original languageEnglish
Pages (from-to)681-686
Number of pages6
JournalJournal of Cellular Physiology
Volume214
Issue number3
DOIs
Publication statusPublished - Mar 2008

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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