Pharmacyclics' Ribozyme Analog For MDR Reversal

21 August 1994

Pharmacyclics of the USA has announced that it has developed, in collaboration with scientists at the University of Texas, a ribozyme analog which may be of use in treating multiple drug resistant tumors. They have reported, for what they claim is the first time, the first example of oligonucleotide-directed, site-specific hydrolysis of RNA using a covalently attached metal complex.

The scientists have developed a short, 20-nucleotide strand of synthetic DNA complementary to an RNA transcript for a multiple drug resistance gene. The antisense strand is conjugated to a europium texaphyrin complex. Through the use of gel electrophoresis, the researchers showed that the ribozyme analog bound to the target RNA transcript and cleaved it at a specific site. The cleaving site was achieved by hydrolysis, at normal physiological temperatures and conditions, and mimicked closely the physiological activity demonstrated by unmodified ribozymes in the body.

The difference between the Pharmacyclics candidate and contemporary antisense approaches is that the oligonucleotide Eu-Tex conjugate not only binds to the desired RNA sequence, it also destroys the template. The researchers believe that this may be a catalytic process, so that the conjugate is not destroyed in the reaction and remains free to break down other transcripts produced by the DNA.

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