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June 2001
Vol. 4, No. 6, p 14.
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Cleaving RNA’s pockets

Binding to the bulge.
Binding to the bulge.
Binding to the bulge. The bulged “binding domain” of the viral Rev-responsive element RNA (right) provides a favorable opening point for the Cu2+-kanamycin A complex (top) to bind to and, subsequently, to cleave. This site-specific cleavage could block the development of RNA viruses.

Despite the great success of antisense and ribozyme/ribonuclease-based technologies in the directed targeting of cellular RNAs, these molecules have long been considered improper targets for the search or design of small-molecule candidate drugs. This is because RNA has been thought to lack well-formed pockets like those found in proteins.

But recent structural analyses of some RNAs have revealed the presence of preorganized intrinsic cavities that could selectively bind small molecules. These findings were confirmed with small organic compounds, including the aminoglycoside antibiotic neomycin B, which recognized and bound to certain structural features in the transactivation-responsive element of HIV-1 RNA (Biochemistry 1998, 37, 14,204–14,212).

Presently, two scientists from Ohio State University, A. Sreedhara and J. A. Cowan, report on the site-specific cleavage of the HIV-1 RNA by the Cu2+-kanamycin A complex, another aminoglycoside compound, at micromolar concentrations and under physiological conditions. (J. Biol. Inorg. Chem. 2001, 6, 166–172). They targeted a segment of viral RNA, the Rev-responsive element (RRE), which contains a bubble-shaped stem-loop structure that is important for virus development. It serves as a recognition site for the Rev protein, which, upon binding to the RRE, facilitates the nucleus-to-cytoplasm transport of HIV-1 mRNA that is required for its translation into viral proteins.

The scientists foundthat the kanamycin A fits well and, thus, selectively binds the RNA “bulged” pocket, while the copper cation performs the hydrolytic function that cuts the designated segment of viral RNA. The specificity of cleavage was demonstrated against a well-defined standard.

The fusion of the binding specificity of aminoglycosides with the cleaving capabilities of the copper cation promises a novel methodology to combat RNA viruses, the cause of many serious disorders.


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