Current wound healing therapies rely on one of three separate approaches:
Our novel approach to facilitate rapid wound healing takes advantage of a mechanism we have newly discovered to enhance mitogenic signalling and promote endogenous ECM production, using inhibition of 14-3-3.
This approach uses a novel class of 14-3-3 inhibitors that disrupts 14-3-3 dimers in a manner that is not reliant on competing with the binding of 14-3-3’s phospho-serine containing client proteins.
14-3-3 proteins act as adaptor proteins to regulate signalling pathways that promote cell proliferation and cell survival, acting as obligate dimers. The 14-3-3 isoform is one of the dominant isoforms expressed in skin and is upregulated significantly in chronic, non-healing wounds such as diabetic ulcers. Furthermore, mice deficient in 14-3-3 exhibited rapid wound healing that was 3-fold faster than that observed in normal control mice. 14-3-3 acts to restrain the activation of Rho-ROCK signalling at wound margins, thereby moderating the production and remodeling of extra-cellular matrix (ECM). Re-establishment of damaged ECM is a key requirement in wound healing as it performs a scaffolding role to support re-epithelialization of the wound and also initiates mechanical signalling pathways required for epidermal cell proliferation. Consequently, inhibiting 14-3-3 activity is an attractive approach to enhance wound healing in chronic wounds.
We used a novel class of molecules that mimic the binding of sphingosine lipid to 14-3-3 at the dimer interface, thereby permitting kinases to access a buried phosphorylation site, phosphorylation of which inhibits 14-3-3 dimerisation. Our studies have revealed that inhibiting 14-3-3 by using these novel molecules accelerates wound healing in a murine model, phenocopying observations in 14-3-3 deficient animals.
We are currently developing pharmacological inhibition of 14-3-3 with the intent of establishing a novel modality for the treatment of chronic wounds.
PCT patent application filed for ‘Modulators of 14-3-3 Functionality and Uses Thereof’ as specification PCT/AU2015000605.
We are seeking co-development partners and technology licensees for the further development of this opportunity