Chemistry and Biochemistry Seminar -CBC Faculty Candidate - Margaret E. Olson, Ph.D. The Scripps Research Institute "Bioorganic Chemistry at the Interface of Immunology and Infectious Disease: Recent Advances in Addiction Vaccines and Botulinum Neurotoxin

Thursday, November 15, 2018
11:45 am
Floor/Room #: 
GP 1002

Bioorganic Chemistry at the Interface of Immunology and Infectious Disease: Recent Advances in Addiction Vaccines and Botulinum Neurotoxin Inhibitors

 

Margaret E. Olson, Ph.D.
NIH Postdoctoral Fellow
Department of Chemistry
The Scripps Research Institute

 

CBC Faculty Candidate

Abstract

Some of the most threatening substances to human health remain void of any therapeutic countermeasures. Efforts during my postdoctoral studies have sought to address two of these unmet clinical needs; namely, substance use disorder (SUD) for stimulant drugs and the lethality of Category A biowarfare agent Botulinum neurotoxin A (BoNT/A). By leveraging synthetic chemistry and chemical biology, next generation vaccines for stimulant misuse and inhibitors for BoNT/A have been developed. Immunopharmacotherapies, or vaccines for drugs of abuse, represent a promising alternative for treating SUD. In this strategy, immunization of a hapten-protein conjugate prompts the immune system to generate highly specific, anti-drug antibodies that minimize drug penetration of the blood-brain-barrier, and thus, psychoactive reward circuit signaling. Because the only SUD vaccines to reach clinical trials have failed, further optimization of vaccine components is required. Efforts to improve hapten design for next-generation methamphetamine vaccines will be discussed. In the second study, strategies to overcome the extraordinarily long half-life of BoNT/A in the neuronal compartment were investigated. While BoNT/A inhibitors with exquisite in vitro potency (low to sub nM) have been discovered, no small molecule has entered clinical trials. To date, most reported BoNT/A inhibitors rely on a non-covalent mechanism of action; however, the long half-life of BoNT/A may ultimately make dosing reversible inhibitors unfeasible. To address BoNT/A persistence, strategies of irreversible inactivation; namely, bifunctional, covalent inhibitors of the BoNT/A light chain have been developed.

DEPARTMENT(S):