Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction

Abstract

Summary(−)-Cocaine is a widely abused drug and there is currently no available anti-cocaine therapeutic. Promising agents, such as anti-cocaine catalytic antibodies and high-activity mutants of human butyrylcholinesterase (BChE), for therapeutic treatment of cocaine overdose have been developed through the structure-and-mechanism-based design and discovery. In particular, a unique computational design strategy based on the modeling and simulation of rate-determining transition state has been developed and used to design and discover desirable high-activity mutants of BChE. One of the discovered high-activity mutants of BChE has a ~456-fold improved catalytic efficiency against (−)-cocaine. The encouraging outcome of the structure-and-mechanism-based design and discovery effort demonstrates that the unique computational design approach based on the transitionstate modeling and simulation is promising for rational enzyme redesign and drug discovery. The general approach of the structure-and-mechanism-based design and discovery may be used to design high-activity mutants of any enzyme or catalytic antibody.

Preparation and in vivo characterization of a cocaine hydrolase engineered from human butyrylcholinesterase for metabolizing cocaine

“…These high-activity mutants of human BChE have been recognized as promising candidates of therapeutic enzymes for anti-cocaine medication. [1–3, 17] In the initial screening of those BChE mutants, the genes of the mutants were transiently expressed for the in vitro and in vivo examination. Further characterization of this enzyme in animal models requires a stable expression cell line efficiently producing the enzyme in large quantity.…”

Synthetic, Switchable Enzymes

“…In 1994, it was conjectured that binding affinity alone might not be a useful way to select potential catalysts and that such candidates should be directly screened for their catalytic activity [Stewart et al, 1994]. More recently, it has been argued that to design such antibodies to catalyze a particular in vivo reaction requires that the catalytic mechanism itself first be understood [Zheng and Zhan, 2008] and, in 2011, it was observed that "attempts to design or synthesise molecules approaching the catalytic efficiency of enzymes have been unsuccessful thus far." [Hammes et al, 2011].…”

Biologics to treat substance use disorders: Current status and new directions

“…167 In contrast to enzymes such as BChE or CocE, it has been challenging to further improve activity of catalytic Ab because their mechanism of action is to stabilize the transition state in non-enzymatic cocaine hydrolysis. 9,18 As a cautionary warning for readers, this section highlights the importance of exploring catalytic Ab as a potential SUD treatment, but it does not provide a detailed review.…”

“…165 From this first report, 165 a variety of strategies to induce catalytic polyclonal Ab through active immunization, or deliver catalytic mAb was examined. 18 Use of catalytic Ab has also been explored for methamphetamine 166 and nicotine. 167 In contrast to enzymes such as BChE or CocE, it has been challenging to further improve activity of catalytic Ab because their mechanism of action is to stabilize the transition state in non-enzymatic cocaine hydrolysis.…”

“…9,18 Cocaine-degrading enzymes derived from human plasma butyrylcholinesterases (BChE) and bacterial cocaine esterases (CocE) have been tested for treatment of cocaine dependence and overdose (NCT01887366, and NCT01846681, Table 1). [148][149][150] These clinical studies showed no evidence of side effects, and provide proof of concept for enzyme-based SUD treatments.…”