14-3-3 proteins act as adaptor proteins to regulate signaling pathways that promote cell proliferation and cell survival, acting as obligate dimers. The 14- 3-3ζ 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 14-3-3ζ exhibited rapid wound healing that was 3-fold faster than that observed in normal control mice.
14-3-3ζ acts to restrain the activation of Rho-ROCK signaling at wound margins, thereby moderating the production and remodeling of the extracellular matrix (ECM). Reestablishment 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 signaling pathways required for epidermal cell proliferation. Consequently, inhibiting 14-3-3 activity is an attractive approach to enhance wound healing in chronic wounds.
Technology Features, Specifications and Advantages
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 revealed that inhibiting 14-3-3 by using these novel molecules accelerates wound healing in a murine model, phenocopying observations in 14-3-3ζ deficient animals.
This technology has applications in wound management, and in the treatment of chronic wounds.
We are currently developing pharmacological inhibition of 14-3-3 with the intent of establishing a novel modality for the treatment of chronic wounds.
We are seeking co-development partners and technology licensees for the further development of this opportunity.
Current wound healing therapies rely on one of three separate approaches:
- preventing infection or,
- providing an external scaffold of extra-cellular matrix or,
- delivery of growth factors to promote epithelial proliferation.
This novel approach to facilitate rapid wound healing takes advantage of a mechanism we have discovered that enhances mitogenic signaling and promotes 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.