Design of peptide-acridine mimics of ribonuclease activity

Ching Hsuan Tung, Ziping Wei, Michael J Leibowitz, Stanley Stein

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Abstract

A series of peptide-acridine conjugates was designed and synthesized, based on three features of the proposed catalytic mechanism of RNase A: 2prime;-proton abstraction by His-12, proton donation to the leaving 5′-oxygen by His-119, and stabilization of the pentacoordinated phosphorous transition state by Lys-41. The substrate binding capability of RNase A was mimicked by the intercalator, acridine. Lysine served as a linker between acridine and the catalytic tripeptide. Cleavage of target RNA was monitored by agarose gel electrophoresis and by gel-permeation chromatography. The carboxyl-amidated conjugates HGHK(Acr)-NH2, HPHK(Acr)-NH2, and GGHK(Acr)-NH2 (where Acr indicates 2-methyl-9-acridinemethylene) all had similar hydrolytic activity. The catalytic mechanism most likely involved only the abstraction of the 2′-proton and stabilization of the transition state. These RNase mimics utilized rRNA and single-stranded RNA but not double-stranded RNA and tRNA as substrates.

Original languageEnglish (US)
Pages (from-to)7114-7118
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number15
StatePublished - 1992
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • General

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