Supplement: 2015 NIDA Summer Research Internship Program

Development of a truly effective anti-cocaine medication has been very challenging, particularly for treatment of cocaine abuse. There is still no FDA-approved medication specific for cocaine abuse. Enhancing cocaine metabolism by administration of butyrylcholinesterase (BChE) has been recognized as a promising treatment strategy for cocaine abuse. However, the catalytic activity of this plasma enzyme is low against the naturally occurring (-)-cocaine. Our integrated computational-experimental effort has led to discovery of high-activity mutants of human BChE, known as cocaine hydrolases (CocHs), with at least 1,000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE. In vivo evidences indicate that our discovered CocHs are promising candidates for development of an anti-cocaine medication. In addition, it has been shown that many cocaine users use heroin along with cocaine. Interestingly, BChE can also hydrolyze heroin to 6-monoacetylmorphine (6-MAM) and 6-MAM to morphine. It is also interesting to determine whether CocHs (BChE mutants) can hydrolyze heroin and 6-MAM and, thus, regulate physiological effects of heroin in rodents (mice and rats). The high school student will be instructed to participate in the studies that aim to understand how CocHs affect the metabolic profiles and physiological effects of cocaine and heroin in rodents, following the corresponding in vitro activity tests. These studies will also help to understand how heroin affects the potency of CocHs in detoxifying cocaine.