Zymedyne’s drug development program targets Cav3.2 T-type calcium channels which are critical contributors to the transmission of pain signals in the afferent pain pathway.  In a wide range of chronic pain conditions these channels are aberrantly upregulated. Work conduced in the Zamponi laboratory revealed that this enhancement is due to a pathological upregulation of the expression of the deubiquitinating enzyme USP5 which associates with the Cav3.2 channels to prevent their degradation.  Zymedyne has a proprietary high throughout screen for small organic disruptors of USP5 binding to Cav3.2, and generated a series of small molecules which inhibit this interaction with high selectivity and affinity, resulting in enhanced degradation of the channels and thus analgesia. Zymedyne’s molecules are highly efficacious in mouse models of acute and chronic inflammatory pain, and in different modalities of neuropathic pain, with no development of tolerance in repeat dosing paradigms.  In addition the mechanism has been independently verified in rats at UC Denver. They key advantage of Zymedyne’s approach is that it targets only those channels that are aberrantly upregulated by USP5, while sparing the normal channel function in other tissues, thus reducing the risk of adverse effects. Zymedyne is now poised to advance one lead molecule to IND enabling studies.