Microbial Enzymes "Eat" Cocaine, Could Be Novel Treatment For Abuse

Efimero, via Wikimedia Commons

Researchers from the University of Kentucky have successfully tweaked a naturally occurring enzyme that breaks down cocaine, improving both its stability in the body and its catalytic efficiency. The team believes that this enzyme could eventually be applied as a potential treatment for both cocaine overdoses and cocaine addiction. The study has been published in Chemical Biology.

Cocaine esterase (CocE) is an enzyme produced by bacteria living in the soil around coca plants. It’s an incredibly efficient biological catalyst that initiates the hydrolysis (breakdown) of cocaine. Researchers have been investigating this protein as a possible candidate for cocaine therapy, but its instability in the body hindered previous efforts. At body temperature the enzyme loses activity within just 12 minutes, making it useless as a therapeutic agent.

Back in 2009, lead researcher Chang-Guo Zhan and colleagues released a study that demonstrated how two mutations introduced into the enzyme can extend the half-life (the amount of time it takes for the activity of the enzyme to reduce by half) to around 6 hours, which could possibly be a long enough window to neutralize the effects of the drug in an individual experiencing overdose.

Unfortunately, however, Zhan explained to Chemical & Engineering News that this is still an insufficient amount of time to be effective as a potential treatment for addiction. In order to be suitable for this, the drug would need to stay in the body for days or even weeks, preventing the user from experiencing the high that they would usually achieve with the drug and thus weaning them off of it.

In an attempt to achieve this stability, the research team ran computer simulations to investigate which part of the enzyme is most affected by high temperatures and then tinkered with these regions. The models revealed that just two amino acid substitutions, from lysine and isoleucine to cysteine, stabilized the structure of the enzyme by introducing extra bonds called disulfide bonds.

When they introduced these mutations into the enzyme, the half-life at body temperature was extended to over 100 days. Furthermore, the catalytic efficiency against cocaine was increased by around 150%.

The team then employed a common method used in drug design to increase the amount of time that the drug remains in the circulation called PEGylation. This process involves the addition polyethylene glycol (PEG) chains to the enzyme. The researchers then tested this modified enzyme in mice and discovered that it fully protected mice from a lethal dose of cocaine for at least three days.

The researchers therefore conclude that, with further development, this enzyme could eventually be used as a valuable tool for the treatment of cocaine abuse. However, much more work needs to be done in order to discern whether the enzyme acts fast enough to prevent the drug from exerting effects on the brain of the user. 

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