Cathepsins are a family of proteases that have been implicated in many diseases.
Virobay compounds are highly potent, orally active and drug-like; addressing common problems in the design of cathepsin inhibitors.
Neuropathic pain manifests when nerves responsible for transmitting pain signals are damaged or dysfunctional, impairing the normal signaling processes. This impairment often results in severe burning, tingling or painful sensations. Affecting more than 15 million people in the US, neuropathic pain is a serious and debilitating condition that is often associated with diabetes mellitus, herpes, HIV, chemotherapy treatment, or trauma. Current therapies are ineffective or only partially effective in many individuals so there is a large unmet medical need for new therapeutics to treat neuropathic pain.
Cathepsin S is activated at the site of injury in models of neuropathic pain induced by surgical nerve damage. Pharmacological inhibition of cathepsin S, either centrally or peripherally, reverses hyperalgesia in these models. Conversely, central administration of recombinant cathepsin S, but not other cathepsins, induces nociception in rodents. It has been demonstrated that cathepsin S is secreted from spinal microglial cells and induces nociception by cleaving fractalkine from the surface of sensory neurons. Free fractalkine subsequently activates microglial cells, contributing to the maintenance of neuropathic pain. Cathepsin S inhibitors are a novel therapeutic approach for the treatment of neuropathic pain.