Oligonucleotide Transition State Analogues of Saporin L3

Eur J Med Chem. 2017 Feb 15;127:793-809. doi: 10.1016/j.ejmech.2016.10.059. Epub 2016 Oct 27.

Abstract

Ribosome inactivating proteins (RIPs) are among the most toxic agents known. More than a dozen clinical trials against refractory cancers have been initiated using modified RIPs with impressive results. However, dose-limiting toxicity due to vascular leak syndrome limits success of the therapy. We have previously reported some tight-binding transition state analogues of Saporin L3 that mimic small oligonucleotide substrates in which the susceptible adenosine has been replaced by a 9-deazaadenyl hydroxypyrrolidinol derivative. They provide the first step in the development of rescue agents to prevent Saporin L3 toxicity on non-targeted cells. Here we report the synthesis, using solution phase chemistry, of these and a larger group of transition state analogues. They were tested for inhibition against Saporin L3 giving Ki values as low as 3.3 nM and indicating the structural requirements for inhibition.

Keywords: Aza-sugar; Oligonucleotide; Ribosome inactivating protein; Saporin; Transition state inhibitor.

MeSH terms

  • Base Sequence
  • Biomimetic Materials / chemistry*
  • Biomimetic Materials / pharmacology*
  • Models, Molecular
  • Oligonucleotides / chemistry*
  • Oligonucleotides / genetics
  • Oligonucleotides / pharmacology*
  • Protein Conformation
  • RNA / genetics
  • RNA / metabolism
  • Ribosome Inactivating Proteins, Type 1 / chemistry*
  • Ribosome Inactivating Proteins, Type 1 / metabolism
  • Ribosome Inactivating Proteins, Type 1 / toxicity
  • Saporins

Substances

  • Oligonucleotides
  • Ribosome Inactivating Proteins, Type 1
  • RNA
  • Saporins