Development of biologic countermeasures for saxitoxin (STX) poisoning
Abstract
Saxitoxin (STX) is an exceptionally lethal paralytic neurotoxin that targets voltage-gated sodium channels (NaVs)1 and is the only marine toxin declared a biological weapon1,2. This naturally-occurring toxin from red tide-associated cyanobacteria and dinoflagellates causes paralytic shellfish poisoning (PSP)1. Despite its extreme lethality, there are no medical countermeasures to mitigate STX poisoning. Select vertebrates, however, are resistant to STX poisoning3-5. The soluble STX binding proteins Saxiphilin (Sxph) and Pufferfish Saxitoxin an Tetrodotoxin Binding Proteins (PTSBPs) are candidate anti-toxins from frogs and fish, respectively, that are thought to sequester STX and mitigate its poisonous action5-7. How such proteins act, and how the STX:anti-toxin complexes are metabolized is unknown. We seek to determine the STX binding properties of a family of frog Sxphs and identify pathways by which they neutralize toxins. Our studies will define the molecular logic of toxin resistance strategies. We will combine structural biology, protein engineering, cell biology, toxin synthesis, and physiological studies to understand how Sxphs endow host organisms with STX resistance and develop proof-of-concept experiments to test the protective effects of Sxphs or engineered versions thereof against STX poisoning. We will use this knowledge to inform anti-STX medical countermeasure development to mitigate poisoning resulting from an STX-based attack.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jun 14, 2022
- Source ID
- HDTRA12110011
Entities
People
- Daniel L Minor
Organizations
- Defense Threat Reduction Agency
- University of California