Circular DNA and DNA/RNA hybrid molecules as scaffolds for Ricin inhibitor design

Matthew B. Sturm, Setu Roday, Vern L. Schramm

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Ricin Toxin A-chain (RTA) catalyzes the hydrolytic depurination of A 4324, the first adenosine of the GAGA tetra-loop portion of 28S eukaryotic ribosomal RNA. Truncated stem-loop versions of the 28S rRNA are RTA substrates. Here, we investigate circular DNA and DNA/RNA hybrid GAGA sequence oligonucleotides as minimal substrates and inhibitor scaffolds for RTA catalysis. Closing the 5′- and 3′-ends of a d(GAGA) tetraloop creates a substrate with 92-fold more activity with RTA (kcat/K m) than that for the d(GAGA) linear form. Circular substrates have catalytic rates (feat) comparable to and exceeding those of RNA and DNA stem-loop substrates, respectively. RTA inhibition into the nanomolar range has been achieved by introducing an N-benzyl-hydroxypyrrolidine (N-Bn) transition state analogue at the RTA depurination site in a circular GAGA motif. The RNA/DNA hybrid oligonucleotide cyclic GdAGA provides a new scaffold for RTA inhibitor design, and cyclic G(N-Bn)GA is the smallest tight-binding RTA inhibitor (K = 70 nM). The design of such molecules that lack the base-paired stem-loop architecture opens new chemical synthetic approaches to RTA inhibition.

Original languageEnglish (US)
Pages (from-to)5544-5550
Number of pages7
JournalJournal of the American Chemical Society
Volume129
Issue number17
DOIs
StatePublished - May 2 2007

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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