Sandbox Reserved 987: Difference between revisions

Cocaine use is a problem with approximately 21 million people abusing it worldwide. ^{<ref>"200 Million People Use Illicit Drugs, Study Finds" Katie Moisse. abcNews Medical Unit. 6 January 2012</ref>} Cocaine mostly affects the brain by inhibiting reuptake of norepinephrine, serotonin, and dopamine ^{<ref>"Cocaine Use and Its Effects" Joseph Goldberg. WebMD Substance Abuse and Addiction Health Center. 23 June 2013</ref>} With these neurotransmitters inhibited from reabsorbing it creates a sense of a "high" for the person using but the "crash" can lead to paranoia, restlessness, and anxiety.

Cocaine Esterase (CocE) is the most efficient protein to hydrolyze the cocaine domain known to date ''in vivo''.^{<ref>"Effects of cocaine esterase following its repeated administration with cocaine in mice" Mei-Chaun Ko, Diwahar Narasimhan, Aaron A. Berlin, Nicholas W. Lukacs, Roger K. Sunahara, James H. Woods. Drug and Alcohol Dependence 1 May 2009;101:202-09. doi: 10.1016/j.drugalcdep.2009.01.002</ref>} Cocaine Esterase is used in bacterium ''Rhodococcus'', which hydrolyzes the cocaine that it uptakes and uses it for carbons and nitrogens. Although this protein metabolizes cocaine in bacterium, it is sure to induce an immune response as it is foreign to the human body. This could mitigate the effects of CocE if a person had suffered from cocaine toxicity.

Cocaine Esterase is a globular protein that is expressed in the cytosol of ''Rhodococcus'' strain of bacteria, containing 574 residues divided into three domains. Domain I is a α/β hydrolase fold-containing domain consisting of residues 1-144 and residues 241-354 with the active site His-287. Domain II is α-helical, consisting of residues 145-240, making up seven helices inserted between β6 and β7 of Domain I. Helices two through six together form a five helix core with helices two and three combine to make a lid-like structure over the active site, His-287. Domain III is made up of residues 355-574 with mostly β-structure including a β-barrel-like core connected by 6 cross over loops, forming a jelly roll-like topology.^{<ref>Narasimhan, D.; Woods, J.H.; Sunahara, R.K. “Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.” ''Future Med Chem.'' 2012, 4, 2: 137-150.</ref>}

The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine was found to last 24 times as long (~4hr 20min)^{<ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref>}

Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.^{<ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref>} Cocaine’s psychological effects occur via binding to neurotransmitter reuptake transporters in the presynaptic nerve termini and blocking them, leading to prolonged presence of neurotransmitters in the synapse.^{<ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref>} Large amounts of dopamine and serotonin in the synapse results in feelings of euphoria and wellbeing. This lingering increase in neurotransmitters within the synapse can lead to self-administration and, therefore, addiction. When cocaine is bound to noradrenergic transporters, elevated noradrenergic signaling occurs, resulting in increased heart rate (HR), blood pressure and vasoconstriction which are often seen in cocaine users.^{<ref>Crumb WJ Jr, Kadowitz PJ, Xu YQ, Clarkson CW. Electrocardiographic evidence for cocaine cardiotoxicity in cat. Can. J. Physiol. Pharmacol. 1990; 68(5):622–625. [PubMed: 2340451]</ref>} Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.^{<ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref>} Cocaine abuse is a serious public health problem. 50% of emergency room visits are due to illicit drug use, cocaine accounts for the majority of those cases.^{<ref>Ball, JK.; Albright, V. National Estimates of Drug-Related Emergency Department Visits. Rockville, MD, USA: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2008</ref>} Interestingly, despite cocaine’s broad use and high addictiveness, there is no US FDA-approved medication for the treatment of cocaine abuse or toxicity. Physicians treat patients enduring cocaine toxicity with standard emergency room agents that control arrhythmias, convulsions and high blood pressure but not with drugs that directly address the toxic levels of cocaine present in the patient.