Pedanius Therapeutics is pioneering a new class of precision medicines - antisense oligonucleotide (ASO) conjugates that has been designed to specifically silence essential genes to treat multi-drug resistant Gram-negative bacterial infections. It utilises a proprietary ligand-mediated technology for the safe and efficient cellular delivery into Gram-negative bacteria. These molecules can be considered the first of a new class of non-conventional RNA-targeted precision medicines for the treatment of Gram-negative infections. A provisional Composition of Matter patent application that has been filed with the UKIPO.
Gene silencing is widespread in nature and was first used as a tool to silence genes in mammalian cells in 2001. Bacteria themselves use natural antisense mechanisms and may be uniquely amenable to antisense control. To date, six ASO drugs have received market authorization by regulatory authorities for indications other than bacterial infections, and at least four drugs are in phase III clinical trials or submitted for market authorization.
Compared to traditional antibiotics, Pedanius lead molecules have immense potential to control the spread of resistant microbes due to its high specificity of action, little risk to human gene expression, and easy design and synthesis. Unlike antibiotics that usually target a universal cellular process and kill bacteria with little selection, these molecules have been shown to target a specific DNA sequence of a bacterial strain without unintended effects on commensal bacteria or other strains. It does this by targeting an essential gene through sequence complementation i.e. via Watson-Crick base pairing. The nucleobase sequences selected for the molecules are within the Shine-Dalgarno (SD) region or ATG/AUG start site of the gene and based on the lowest number of off-target hits in other genes in bacteria and eukaryotes; Unfavourable properties such as CG motif, hairpin motifs, tetraplexes were avoided. Given the short sequence, these molecules have no effect on eukaryotic genes, hence minimising off target effects in human. In addition, these molecules, as ASOs, is not subject to efflux pumps and/or the development of resistance.
Proprietary Delivery Technology
ASOs as anti-bacterials have been largely unexplored primarily due to the poor uptake efficiency of antisense molecules by bacteria. Efficient delivery of ASOs to their site of action and into bacteria with enough concentration has been a major obstacle, which has greatly hampered their clinical application. A single versatile and safe system suitable for efficient delivery of ASOs would be particularly useful. Akin to the liver targeting technologies of the leading publicly-listed RNAi companies, Pedanius lead molecules uses a proprietary carrier technology where the ASO is conjugated via a linker to an endogenous carbohydrate ligand that is recognised by a receptor on the outer membrane of Gram-negative bacteria for a fast facilitated delivery into bacteria. This receptor is highly selective for this endogenous carbohydrate, which is essential for bacterial cell membrane synthesis and survival. To date, no mutations in this selective receptor has been evidenced in the literature.
Antisense Oligonucleotide Medicinal Chemistry
The lead molecules are based on using phosphoro-diamidate morpholino oligomer (PMO) chemistry that has been pioneered by Sarepta Therapeutics (marketed drug eteplirsen). PMOs are synthetic chemical structures modelled after the natural framework of RNA. They have the same nucleic acid bases found in RNA but are bound to six-sided morpholine rings instead of five-sided ribose rings. The morpholine rings are connected to each other by phosphoro-diamidate linkages instead of the phosphodiester linkages found in RNA.
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