The advantages of Spirogen's patented technology are:
- Uses DNA as a target rather than RNA or proteins
- Low molecular weight Molecules made using a combinatorial strategy
- Molecules bind to DNA covalently rather than non-covalently
- Molecules can penetrate the cellular and nuclear membranes
Uses DNA as a target rather than RNA or proteins
DNA is regarded as a superior target to RNA or proteins for drug discovery. During the process of gene expression, the gene, which is composed of DNA, may be transcribed many times to create thousands of RNA molecules, each of which may be translated many times to create vast numbers of protein molecules which are the targets of most current therapeutic strategies. In the case of strategies aimed at targeting the RNA or protein, to maximize the efficiency of the protein knockout process, a large number of drug molecules (ideally stoichiometric) is necessary so that all copies of the RNA or protein are intercepted. However, with the gene targeting approach, given that there are only two copies of any given gene per cell, it is theoretically possible to completely abolish production of a specific protein with just two molecules of a DNA-targeted agent. This means that much lower doses of a gene-targeted compared to a RNA- or protein-targeted agent is likely to be required in order to provide a given therapeutic response. The high potency of steroids, which operate at the DNA level through nuclear receptors, is thought to be a good example of the efficiency gain possible through this approach. Also since Spirogen's approach is specific for a particular gene, it has the advantage of modulating the activity of the relevant gene without effecting the majority of proteins necessary for normal cellular functions. Hence, drugs based on this technology should have minimal side effects.
Low molecular weight molecules made using a combinatorial strategy
Spirogen's combinatorial chemistry approach allows rapid production of low molecular weight organic compounds capable of targeting genes in a sequence-specific manner thus causing their down- or up-regulation. This is advantageous over other approaches which involve building molecules by the traditional step-wise approach which can involve a significant time element as well as a degree of trial and error. These agents also have the desirable pharmacological and pharmaceutical properties associated with small molecule drugs such as a low cost of manufacture, convenience in delivery, and favourable bioavailability. They are also stable and can be rapidly identified and synthesized through solid phase and combinatorial approaches.
Molecules bind to DNA covalently rather than non-covalently
Spirogen's gene targeting agents are designed to bind in the minor groove of double stranded DNA and to block transcription in a highly sequence-selective fashion. Although these molecules fit snugly in the minor groove without causing distortion to the DNA helix, they are apparently capable of efficiently blocking the progress of RNA polymerase as it moves along the helix thus interfering with transcription elongation. In contrast, molecules which bind non-covalently to DNA are unable to block the progress of polymerases, as these enzymes push them out of the groove as they progress. Therefore, Spirogen is in a unique position to offer molecules that can inhibit transcription by either blocking the binding of transcription factors or the process of transcription elongation (or both). Furthermore, by inhibiting the binding of suppressor proteins, it should be possible to up-regulate gene expression as well.
Molecules can penetrate the cellular and nuclear membranes
Spirogen's approach produces substantially lower molecular weight molecules than antisense oligonucleotides or zinc-finger proteins. Therefore unsurprisingly recent experiments demonstrate that they readily cross both cell and nuclear membranes thus allowing them to specifically modulate gene expression which is a feature that clearly differentiates them from competitor molecules.
