Rational Drug Development Using Gene-Targeted Agents and Their Application in Anti-Gene Radiotherapy

摘要

Currently rational drug design is limited to using protein targets in the design and production of therapeutic agents. However, many genetic and infectious diseases may not be adequately treated with this approach. In these circumstances the DNA sequence of an offending gene is itself a potential target for rational drug development. Genetargeted therapeutic strategies require the development of ligands that can recognize and bind unique DNA targets sequence specifically. Several approaches have been described for the development of sequence-specific DNA targeting agents. These include synthetic polyamides that recognize and bind to DNA in the minor groove, peptide nucleic acids which can penetrate the DNA duplex and form a P-loop, or a triple-helical structure with one of its strands, and triplehelix (triplex) forming oligonucleotides which bind to the major groove of duplex DNA at polypyrimidine / polypurine sequences. Of these, Triplex-Forming Oligonucleotides (TFOs) are the most extensively characterized synthetic ligands capable of recognizing and binding sequence specifically to duplex DNA. Consequently, they have been the focus of a new gene therapy strategy that we call ‘anti-gene radiotherapy’. This strategy employs TFOs labeled with Auger-electronemitting radionuclides to produce sequence-specific DNA double strand breaks that ultimately lead to gene inactivation following repair. Anti-gene radiotherapy is made possible by the highly localized damage produced by decay of an Augeremitter, such as 125I, and the sequence specific positioning of DNA damage made possible by TFOs. This report will address recently described strategies that employ these gene-targeting methods to alter target gene expression or structure, with particular emphasis being paid to the use of TFOs in anti-gene radiotherapy.