Modified RNAs as potential drug targets.
Bleomycin (BLM) is a natural antibiotic that is effective in treatment of selected cancers. Although the exact therapeutic mechanism of bleomycin is not known, its target is thought to be a nucleic acid. Besides cleaving DNA, in vitro, Fe-bleomycin cleaves the anticodon of yeast tRNA(Phe) specifically. Using CD and fluorescence spectroscopy we have found that apo-bleomycin binds to synthetic RNA analogs of the anticodon of yeast tRNA(Phe) with an affinity similar to that previously reported for DNA. In order to understand BLM's selectivity, the role magnesium ions play in RNA recognition should be explained. Many RNA substrates for Fe-BLM, including yeast tRNA(Phe), are not cleaved by the drug when the Mg2+ concentration exceeds 1 mM. Competition experiments with anticodon analogs provide insight into the role of magnesium ions in RNA recognition by BLM. These simple modified RNAs may be useful as model systems for investigating BLM/RNA recognition and development of highly selective drugs toward RNA targets.
Guenther
R
R
Department of Biochemistry, North Carolina State University, Raleigh 27695, USA.
Forrest
B
B
Newman
W
W
Małkiewicz
A
A
Agris
P F
PF
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000926:Anticodon / Q000187:drug effects*; D001761:Bleomycin / Q000494:pharmacology*; D002942:Circular Dichroism; D015394:Molecular Structure; D012331:RNA, Fungal / Q000187:drug effects*; D013050:Spectrometry, Fluorescence
D000903:Antibiotics, Antineoplastic; D000926:Anticodon; D012331:RNA, Fungal; D001761:Bleomycin