Strychnine is a poisonous indole alkaloid isolated from the seeds of the Indian tree Strychnos nux vomica. It is also one of the most bitter known substances and the taste can be detected as low as 1ppm. Strychnine is mainly used as a pesticide to control rats, moles, gophers and coyotes. It is colorless and odorless. It is highly toxic and the lethal dose for human adults ranges between 30-120 mg. Strychnine is a potent antagonist for the inhibitory glycine receptor, a ligand-gated chloride channel in the spinal cord and the brain. It can cause muscular convulsions and eventually death through asphyxia and exhaustion. Unfortunately there is no antidote for strychnine. Treatments for strychnine poisoning are primarily supportive and symptomatic care. At acidic pH (stomach), strychnine is ionized and rapidly and completely absorbed in the small intestine. In strychnine poisoning, the tissues with the highest strychnine concentrations are the blood, liver and kidneys. Strychnine is metabolized in the liver by microsomal enzymes and its metabolites are eliminated from the body via the kidney into the urine. Biological half-life in humans is about 10-12 hours. Up to 20% is excreted unchanged in the urine within 24 hours. Since a significant portion of the ingested strychnine stay in the blood in the first 24 hours, a high-affinity capturing molecule for strychnine could potentially be used as antidote for strychnine poisoning. We hypothesize that: (i) Peptidic or peptidomimetic molecules that bind strongly to strychnine can be efficiently identified by screening OBOC combinatorial libraries, and (ii) Such high affinity capturing agents can be used as antidote against strychnine poisoning. The overall goal of this R21 grant is to use encoded OBOC combinatorial libraries to develop and characterize high affinity capturing agents against strychnine. In vivo testing of the capturing agents as antidote for strychnine, however, is beyond the scope of the grant proposal, and will be the subject of subsequent grant application.
Strychnine is a poisonous indole alkaloid isolated from the seeds of the Indian tree Strychnos nux vomica. Unfortunately there is no antidote for strychnine. Treatments for strychnine poisoning are primarily supportive and symptomatic care. We shall apply the enabling OBOC combinatorial library method to discover antidotes for strychnine. Based on the primary screening results, secondary and tertiary OBOC combinatorial libraries will be designed, synthesized and screened under higher stringency condition for further optimization of the lead compounds. The binding affinity as well as interaction mode between strychnine and the capturing agents will be fully characterized.