CHIRAL TECHNOLOGIES
New technology for stereoisomeric synthesised drugs
NOXXON Pharma is a biopharmaceutical company developing a new class of proprietary therapeutics called Spiegelmers, a chemically synthesised, non-immunogenic alternative to antibodies. The Spiegelmer platform has generated a number of lead oligonucleotide compounds that are under preclinical investigation as well as a diversified portfolio of clinical-stage therapeutics.
A
significant pitfall to the optimisation of RNA aptamers as therapeutics is the instability of RNA. As such, a PhD project at the Free University Berlin in the late 1990s researched how best to solve this issue. The researchers took a novel approach that combined the evolutionary screening technology known as SELEX (systematic evolution of ligands by exponential enrichment) with the use of mirror-image RNA made from non-natural, mirror-image L-nucleotides. The research and subsequent analysis demonstrated that a) functional mirror-image RNA oligonucleotides were generated and that b) such molecules displayed the expected high biostability in a biological environment. On that basis, NOXXON Pharma AG was formed to exploit this drug discovery platform in order to identify better RNA-based therapeutics, which were named Spiegelmers from the German word ‘Spiegel’, meaning ‘mirror’.
Mirror-image oligonucleotides Spiegelmers are mirror-image oligonucleotides either consisting of L-RNA or L-DNA building blocks, and therefore these molecules have the exact mirror-image behaviour compared to natural nucleic acids. The phenomenon of ‘handedness’ or chirality is an important property of a large number of organic chemical compounds and the majority of small-molecule drugs are chiral. However, apart from NOXXON’s drug candidates, fully functional mirror-image macromolecules based on either a nucleic acids backbone or made from amino acids are not yet in development.
It is important to note that Spiegelmers cannot base-pair with natural RNA or DNA, nor do they interact with the components of the immune system that normally react to extracellular nucleic acids (for example, the toll-like receptors or TLRs). The founders of NOXXON started with an in-licensed patent application that was
38 sp2 Inter-Active July/August 2012
generated at the Free University Berlin. As with other platform technologies, overlapping and complementing IP has been added to the NOXXON portfolio, giving the company full freedom-to-operate which, in turn, it can pass on to its partners.
Screening for functional structures “The basis for the identification of new Spiegelmers is the screening of vast oligonucleotide libraries for functional structures. The enormous diversity of these libraries almost guarantees that a few sequences will fold into a suitable structure that can bind and inhibit a target molecule of interest. It is assumed that the larger the size of the library the higher the likelihood of finding a well-suited sequence as a drug candidate lead. The huge number of sequences can be easily handled through means of PCR (polymerase chain reaction) and even if only a single molecule in the starting library may provide the desired properties, powerful PCR may be able to help to select it from the ‘noise’ of other
sequences,” explains NOXXON’s CSO, Dr Sven Klussmann. “The screening of libraries is performed using natural D-RNA on a mirror-image target, for example a D-amino acid protein. Once the candidate is identified, the corresponding sequence is used but made with L-oligonucleotides and it is this therapeutic which binds to the natural target, for example an L-amino acid protein.”
Desirable properties
As described above, the SELEX process is an evolutionary screening technique to identify functional structures (aptamers or their mirror- image counterpart: Spieglemers) based on short nucleic acid sequences. These oligonucleotide structures can be used to block strong pathological protein-protein interactions very efficiently. As such, their properties in terms of affinity and selectivity are comparable to those of monoclonal antibodies and other protein-based scaffolds. A major point of differentiation, however, is the immunogenicity of the products. Whereas oligonucleotides with a natural configuration
Conventional RNA aptamers vs Spiegelmers.
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