Toxin-Drug Conjugates: structural and functional studies of Protoxin-II (360G-Wellcome-109073_Z_15_A)

Chronic pain affects a large number of patients worldwide but the available treatment options are often far from adequate. The voltage-gated sodium channel Nav1.7 has been identified as a target for drugs to treat nociceptive chronic pain, but as yet no clinical candidates have been identified. Protoxin-II is a small protein found in the venom of the Peruvian green velvet tarantula, and is a potent and specific inhibitor of Nav1.7; it is therefore a promising lead as a drug for chronic pain. However, many crucial aspects of the interaction of Protoxin-II with Nav1.7 remain unknown: it is not known where the toxin binds to Nav1.7 and how this binding mode effects inhibition of the channel, or how Protoxin-II is able to select for Nav1.7 over other voltage-gated sodium channels. This project will attempt to develop an efficient and versatile synthetic route to Protoxin-II and analogues, and to use these analogues to test the structure-function relationship in Protoxin-II. This information will be used to probe its method and site of action against Nav1.7, and to design ‘toxin-drug conjugates’, analogous with antibody-drug conjugates used as treatments for cancer, with high therapeutic potential.