Long-Lasting Enzyme Chews Up Cocaine | Chemical & Engineering News
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Web Date: June 23, 2014

Long-Lasting Enzyme Chews Up Cocaine

Biochemistry: Researchers increase the stability and efficiency of a natural enzyme that breaks down cocaine, offering a potential treatment for overdose and addiction
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE
Keywords: cocaine, addiction, overdose, computational protein design, cocaine esterase
Breaking The Habit
Biochemists think engineered cocaine esterase (CocE), which hydrolyzes cocaine (left) into ecgonine methyl ester and benzoic acid, could be a way to treat cocaine overdoses and addiction.
Credit: Chang-Guo Zhan
Breaking The Habit
Biochemists think engineered cocaine esterase (CocE), which hydrolyzes cocaine (left) into ecgonine methyl ester and benzoic acid, could be a way to treat cocaine overdoses and addiction.
Credit: Chang-Guo Zhan

Despite cocaine’s undeniable destructiveness, there are no antidotes for overdoses or medications to fight addiction that directly neutralize cocaine’s powerful effects. A natural bacterial enzyme, cocaine esterase, could help by chopping up cocaine in the bloodstream. But the enzyme is unstable in the body, losing activity too quickly to be a viable treatment. Now, using computational design, researchers tweaked the enzyme to simultaneously increase stability and catalytic efficiency (ACS Chem. Biol. 2014, DOI: 10.1021/cb500257s).

Cocaine esterase, originally isolated from bacteria living in the soil near coca plants, hydrolyzes cocaine with high efficiency, destroying the drug’s potency. However, the half-life of the protein is only 12 minutes at body temperature. “It would be hard to use this enzyme for therapeutic purposes,” says Chang-Guo Zhan of the University of Kentucky.

In a previous study, Zhan introduced two mutations to cocaine esterase, extending the half-life of the enzyme to about six hours—long enough, perhaps, to treat an overdose (Mol. Pharmacol. 2009, DOI: 10.1124/mol.108.049486). However, six hours isn’t enough, Zhan says, to treat addiction. For that, he’d want an enzyme that could remain circulating in the bloodstream for days or weeks, blocking the cocaine high so that an addict could break the habit. So Zhan’s team turned to a computational approach that could identify additional structural modifications to further increase cocaine esterase’s stability.

The researchers first identified the enzyme’s greatest weakness under rising temperatures. The team studied a computational model of the enzyme as it was heated from 10 to 300 K, looking for the part of the enzyme that unraveled first. They then tested mutations to make that region stable, while also ensuring that their changes didn’t alter the active site’s flexibility, which is critical for catalysis. In the end, the researchers needed just two changes: They made two cysteine mutations in the vulnerable core of the enzyme to form a disulfide bond. This molecular crossbeam increased the in vitro half-life of cocaine esterase to 100 days, while also boosting catalytic efficiency by 150%.

Zhan’s team next tested the enzyme’s stability in the bloodstreams of mice. They attached polyethylene glycol to the surface of the mutant enzyme, which is a common chemical trick drug designers use to improve the in vivo half-life of protein-based drugs. Mice injected with the tagged enzyme survive daily lethal doses of cocaine for an average of 94 hours.

S. Michael Owens of the University of Arkansas for Medical Sciences says the enzyme looks hopeful for treating overdoses. It also may work to treat addiction, he says, but additional research is needed to determine if the enzyme works fast enough to eliminate cocaine in the body before it can have its effect in the brain.

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Aaron Vollrath  (June 24, 2014 2:45 PM)
This is a very interesting approach. The question I would have is how the adaptive immune system of the mouse responds to the presence of this foreign enzyme? This may have utility in acute overdose settings, but long-term administration for addiction might not be feasible due to development of neutralizing antibodies.
Zeke Ortiz  (July 3, 2014 11:24 PM)

Not only that, but this enzyme would be blocked by one Cocaine molecule, and therefore, just MAO and the CYP450 enzymes - if you took another chemical that could occupy this enzyme - Cocaine would run freely through-out the body anyways.

Sure, it's one hour half-life would not be affected (unless someone took another drug that would occupy CYP3A4 - like the Over The Counter, H2 blocker, Cimetidine (trade name Tagamet).

Personally - I do not believe that introducing an enzyme that would break down Cocaine, and Cocaine only would be of any benefit. Users of Cocaine would move on to other stimulants. Amphetamine's are much easier to get than Cocaine. For instance - a gram of Methylone (an amphetamine-cathinone derivative that's very similar to Cocaine in the fact that it's a TRI) only costs $40, while a gram of Cocaine costs $80 dollars (all of those are just national averages, however).

Anyways, many Cocaine users would probably switch to Methylone since it's half-life is longer, it's cheap, easy to manufacture, entirely synthetic, and as of this post's date... not illegal.

Although, a court may still be able to press charges since Methylone is an analogue of Amphetamine, Methamphetamine, and is the direct - acetylation derivative of MDMA.

But that's not my point to be honest. My point is - there are plenty of stimulants to replace Cocaine. Ritalin (Methylphenidate) would be the most likely candidate, since it's mechanism of action is entirely identical to that of Cocaine, just without the Serotonergic actions.
CGZ  (June 28, 2015 1:09 AM)
The following Editorial has clearly explained why the enzyme therapy approach is promising for treatment of cocaine addiction and overdose:

"Are pharmacokinetic approaches feasible for treatment of cocaine addiction and overdose?", Zheng F and Zhan CG, Future Med. Chem. 2012, 4(2): 125-128. doi: 10.4155/fmc.11.171.

Please let me know if you still have any questions after you read the above Editorial.
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