Enzyme-Therapy Approaches for the Treatment of Drug Overdose and Addiction

Zheng, Fang; Chen, Zhan

doi:10.4155/fmc.10.275

Cited by 31 publications

(23 citation statements)

References 46 publications

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“…The catalytic activity of WT hBChE against cocaine is measurable, albeit slow, and provides one of the major detoxification pathways for the drug, generating non-psychoactive metabolites 10 , 11 . Mutants of BChE have been rationally-designed, creating highly efficient recombinant cocaine hydrolases aimed toward an enzyme-based therapy to treat drug overdose and addiction 12 – 19 . When designing BChE-based cocaine hydrolase mutants, care was taken to ensure that their ability to hydrolyze the crucially important substrate, acetylcholine (ACh), was not significantly enhanced.…”

Section: Introductionmentioning

confidence: 99%

Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity

Larrimore

Kazan

Kannan

et al. 2017

Sci Rep

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Butyrylcholinesterase (BChE) is an enzyme with broad substrate and ligand specificities and may function as a generalized bioscavenger by binding and/or hydrolyzing various xenobiotic agents and toxicants, many of which target the central and peripheral nervous systems. Variants of BChE were rationally designed to increase the enzyme’s ability to hydrolyze the psychoactive enantiomer of cocaine. These variants were cloned, and then expressed using the magnICON transient expression system in plants and their enzymatic properties were investigated. In particular, we explored the effects that these site-directed mutations have over the enzyme kinetics with various substrates of BChE. We further compared the affinity of various anticholinesterases including organophosphorous nerve agents and pesticides toward these BChE variants relative to the wild type enzyme. In addition to serving as a therapy for cocaine addiction-related diseases, enhanced bioscavenging against other harmful agents could add to the practicality and versatility of the plant-derived recombinant enzyme as a multivalent therapeutic.

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Section: Introductionmentioning

confidence: 99%

Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity

Larrimore

Kazan

Kannan

et al. 2017

Sci Rep

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“…An enzyme therapy 1 2 3 4 such as uricase (UCU) application represents an alternative strategy which is more effective than the traditional chemotherapy. The incidences of hyperuricaemia and its related diseases have been growing fast worldwide 5 6 .…”

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confidence: 99%

Uricase alkaline enzymosomes with enhanced stabilities and anti-hyperuricemia effects induced by favorable microenvironmental changes

Zhou

Zhang

et al. 2016

Sci Rep

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Enzyme therapy is an effective strategy to treat diseases. Three strategies were pursued to provide the favorable microenvironments for uricase (UCU) to eventually improve its features: using the right type of buffer to constitute the liquid media where catalyze reactions take place; entrapping UCU inside the selectively permeable lipid vesicle membranes; and entrapping catalase together with UCU inside the membranes. The nanosized alkaline enzymosomes containing UCU/(UCU and catalase) (ESU/ESUC) in bicine buffer had better thermal, hypothermal, acid-base and proteolytic stabilities, in vitro and in vivo kinetic characteristics, and uric acid lowering effects. The favorable microenvironments were conducive to the establishment of the enzymosomes with superior properties. It was the first time that two therapeutic enzymes were simultaneously entrapped into one enzymosome having the right type of buffer to achieve added treatment efficacy. The development of ESU/ESUC in bicine buffer provides valuable tactics in hypouricemic therapy and enzymosomal application.

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“…One type of protein drugs is the enzyme therapy which aims to detoxify the toxic compounds (such abused drugs) in the body. For example, the FPCM-based firstprinciples QM calculations [97,106] on the reaction mechanism for the non-enzymatic hydrolysis of cocaine in solution were followed by further MD simulations and QM/MM calculations [31,[128][129][130][131][132] on the detailed mechanism for the enzymatic hydrolysis of cocaine, leading to discovery of highly efficient cocaine hydrolases [133][134][135][136][137][138] as promising candidates for anti-cocaine therapeutics [139][140][141][142][143][144][145]. The first one [133] of these cocaine hydrolases discovered by Zhan's group has already been developed into an investigational new drug (known as TV-1380) by Teva Pharmaceutical Industries Ltd; the outcomes of the human clinical trials have revealed that this new drug is safe and efficacious for human [146].…”

Section: Design New Drugs Based On Computational Modeling Of Protein-mentioning

confidence: 99%

“…The encouraging outcomes of the drug discovery and development efforts based on computational modeling have demonstrated that computational drug design is valuable not only for small-molecule drug discovery, but also for protein drug discovery and development [139][140][141][142][143][144]151].…”

Section: Design New Drugs Based On Computational Modeling Of Protein-mentioning

confidence: 99%

Computational Modeling of Solvent Effects on Protein-Ligand Interactions Using Fully Polarizable Continuum Model and Rational Drug Design

Zheng

Chen

2013

Commun. comput. phys.

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This is a brief review of the computational modeling of protein-ligand interactions using a recently developed fully polarizable continuum model (FPCM) and rational drug design. Computational modeling has become a powerful tool in understanding detailed protein-ligand interactions at molecular level and in rational drug design. To study the binding of a protein with multiple molecular species of a ligand, one must accurately determine both the relative free energies of all of the molecular species in solution and the corresponding microscopic binding free energies for all of the molecular species binding with the protein. In this paper, we aim to provide a brief overview of the recent development in computational modeling of the solvent effects on the detailed protein-ligand interactions involving multiple molecular species of a ligand related to rational drug design. In particular, we first briefly discuss the main challenges in computational modeling of the detailed protein-ligand interactions involving the multiple molecular species and then focus on the FPCM model and its applications. The FPCM method allows accurate determination of the solvent effects in the first-principles quantum mechanism (QM) calculations on molecules in solution. The combined use of the FPCM-based QM calculations and other computational modeling and simulations enables us to accurately account for a protein binding with multiple molecular species of a ligand in solution. Based on the computational modeling of the detailed protein-ligand interactions, possible new drugs may be designed rationally as either small-molecule ligands of the protein or engineered proteins that bind/metabolize the ligand. The computational drug design has successfully led to discovery and development of promising drugs.

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Enzyme-Therapy Approaches for the Treatment of Drug Overdose and Addiction

Abstract: “Recent progress in the study of cocaine-metabolizing enzymes demonstrates that enzyme-therapy approaches using appropriately designed enzymes show promise for the treatment of drug overdose and addiction.”

Cited by 31 publications

References 46 publications

Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity

Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity

Uricase alkaline enzymosomes with enhanced stabilities and anti-hyperuricemia effects induced by favorable microenvironmental changes

Computational Modeling of Solvent Effects on Protein-Ligand Interactions Using Fully Polarizable Continuum Model and Rational Drug Design

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