Synthetic modification of a natural toxin, gonyautoxin 2/3, is enabling the development of new therapies for painful neuromuscular disorders, such as anal fissure and chronic tension-type headache. Gonyautoxins target voltage-gated Na+ ion channels, a family of integral membrane proteins responsible for the transmission of signals along electrically conducting cells. Preliminary human clinical trials conducted with gonyautoxin 2/3 and a closely related compound, neosaxitoxin, indicate that these species have superior efficacy and fewer side effects than existing pharmacological treatment options for anal fissure, chronic tension-type headache, postoperative pain, and other medical conditions. Despite compelling data in >300 human subjects, limited availability from natural sources and a low margin of safety are major obstacles to the clinical development of either species. Site One has technology in place to prepare analogues of the natural toxins by chemical synthesis from inexpensive starting materials. We have prepared ~100 modified compounds at seven position around the core structure, and have identified analogues showing an improved margin of safety and extended duration of action in in vivo models measuring local anesthesia and inhibition of muscle contraction. The overarching aim of our proposal is to evaluate a small collection of our most promising compounds, and to select a single drug candidate meeting specific safety and efficacy criteria for advancement to pre-clinical development.
Chronic tension type headache and anal fissure are debilitating medical conditions for which existing treatment options are inadequate. A family of naturally occurring molecules derived from algae has shown excellent efficacy in human clinical trials for both indications with no serious side effects, however, concerns over the low safety margin of these species have hindered development. We aim to develop a safer, more effective therapy for anal fissure and chronic tension headache by modification of these natural compounds.