Organophosphate detoxification by membrane-engineered red blood cells

Smith, Paige N.; Mao, Leran; Sinha, Kaustubh; Russell, Alan J.

doi:10.1016/j.actbio.2021.01.043

Cited by 9 publications

(5 citation statements)

References 47 publications

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“…In a previous study, we successfully adopted the iso-reactivity model to determine amine PEGylation kinetics for butylcho-linesterase. 16 Our fitted parameters agreed with experimental findings, with monoPEGylated BChE being the dominant conjugate under the performed reaction conditions (Figure 2 A−B).…”

Section: ■ Results and Discussionsupporting

confidence: 88%

Moving Protein PEGylation from an Art to a Data Science

2022

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PEGylation is a well-established and clinically proven half-life extension strategy for protein delivery. Protein modification with aminereactive poly(ethylene glycol) (PEG) generates heterogeneous and complex bioconjugate mixtures, often composed of several PEG positional isomers with varied therapeutic efficacy. Laborious and costly experiments for reaction optimization and purification are needed to generate a therapeutically useful PEG conjugate. Kinetic models which accurately predict the outcome of socalled "random" PEGylation reactions provide an opportunity to bypass extensive wet lab experimentation and streamline the bioconjugation process. In this study, we propose a protein tertiary structure-dependent reactivity model that describes the rate of protein-amine PEGylation and introduces "PEG chain coverage" as a tangible metric to assess the shielding effect of PEG chains. This structure-dependent reactivity model was implemented into three models (linear, structure-based, and machine-learned) to gain insight into how protein-specific molecular descriptors (exposed surface areas, pK a , and surface charge) impacted amine reactivity at each site. Linear and machine-learned models demonstrated over 75% prediction accuracy with butylcholinesterase. Model validation with Somavert, PEGASYS, and phenylalanine ammonia lyase showed good correlation between predicted and experimentally determined degrees of modification. Our structure-dependent reactivity model was also able to simulate PEGylation progress curves and estimate "PEGmer" distribution with accurate predictions across different proteins, PEG linker chemistry, and PEG molecular weights. Moreover, in-depth analysis of these simulated reaction curves highlighted possible PEG conformational transitions (from dumbbell to brush) on the surface of lysozyme, as a function of PEG molecular weight.

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Section: ■ Results and Discussionsupporting

confidence: 88%

Moving Protein PEGylation from an Art to a Data Science

2022

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Section: Demonstrated Applicationsmentioning

confidence: 99%

“…[ 139 ] For example, RBCs were surface‐functionalized with butyrylcholinesterase (BChE) to serve as an enhanced prophylactic treatment against nerve agent toxicity (Figure 7b). [ 140 ] BChE is a potential antidote against poisoning by organophosphate nerve agents, but its rapid metabolism and clearance in the body necessitate higher doses and more frequent administration. In this study, RBC surfaces were first chemically modified to present thiol groups using Traut's reagent (2‐iminothiolane), and then, the TMMA reaction with maleimide‐terminated, PEGylated BChE (BChE‐PEG‐Mal) led to the construction of RBC@BChE.…”

Section: Demonstrated Applicationsmentioning

confidence: 99%

“…[139] For example, RBCs were surface-functionalized with butyrylcholinesterase (BChE) to serve as an enhanced prophylactic treatment against nerve agent toxicity (Figure 7b). [140] BChE is a potential antidote against poisoning by organophosphate nerve agents, but its rapid metabolism and clearance in the body necessitate higher (blue) whole blood with RBC@BChE. Reproduced with permission.…”

Section: Drug Delivery Systemsmentioning

confidence: 99%

mentioning

confidence: 99%

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Bioempowerment of Therapeutic Living Cells by Single‐Cell Surface Engineering

Yang

Choi

Nguyen

et al. 2023

Advanced Therapeutics

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Living cells have the irreplaceable capability to achieve a wide range of complex biochemical reactions precisely and efficiently, which makes them attractive materials for therapeutic applications. In lieu of the traditional biochemical and biological approaches primarily focused on the augmentation of the innate functions of cells, there has been appreciable progress in the development of engineered therapeutic cells, mainly based on the chemical modifications of cell surfaces, at the single‐cell level, which empowers individual living cells with designed therapeutic functions in a cytocompatible manner. This review highlights the latest advances in the development of therapeutic living cells using single‐cell surface engineering, for potential applications in blood transfusion, drug delivery, cancer therapy, probiotic therapy, and tissue engineering and regenerative medicine. The methodological strategies for functionalizing cell surfaces with biomolecules, and inorganic and organic materials, to endow living cells with extrinsic physicochemical and biological properties as well as to increase the durability and efficacy of engineered therapeutic cells, are also briefly overviewed. The review ends with a perspective that discusses the construction of active cell‐in‐shell nanobiohybrid systems, in which exogenous materials formed on cell surfaces mutually and intimately communicate with the cells inside, as a future research direction for single‐cell surface engineering.

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Management and Modulation of Cholinesterase

Ranjan

Jindal

2021

Toxicology of Organophosphate Poisoning

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Organophosphate detoxification by membrane-engineered red blood cells

Cited by 9 publications

References 47 publications

Moving Protein PEGylation from an Art to a Data Science

Moving Protein PEGylation from an Art to a Data Science

Bioempowerment of Therapeutic Living Cells by Single‐Cell Surface Engineering

Management and Modulation of Cholinesterase

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