Click and release: bioorthogonal approaches to “on-demand” activation of prodrugs

Ji, Xingyue; Pan, Zhixiang; Yu, Bingchen; Cruz, Ladie Kimberly De La; Zheng, Yueqin; Ke, Bowen; Wang, Binghe

doi:10.1039/c8cs00395e

Cited by 225 publications

(201 citation statements)

References 112 publications

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“…3,4 These reactions have opened unprecedented possibilities in chemical biology and drug delivery. 5,6 Dissociative bioorthogonal chemistry has been applied to the on-demand dissolution of polymers and micelles, 7-9 site-specic actuation of prodrugs, [10][11][12] and control of enzyme activity in vivo. [13][14][15] Although a growing number of "click-to-release" reactions [16][17][18][19][20][21][22][23] has provided a solid foundation for applications in the life sciences, extending the reaction scope will be necessary to access the full range of capabilities.…”

Section: Introductionmentioning

confidence: 99%

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

Svatunek

Parvez

et al. 2020

Chem. Sci.

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Section: Introductionmentioning

confidence: 99%

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

Svatunek

Parvez

et al. 2020

Chem. Sci.

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“…The implications of our model will likely still hold if prodrug transport is not the rate limiting step (i.e., represents a separate mechanism by which bacteria can escape treatment) and is greater than the rate of prodrug activation. This is a reasonable assumption given that the rates of drug 5 diffusion across membranes 48,49 are on the order 10 10 -10 17 -fold higher than the typical range of prodrug activation rates 50,51 .…”

Section: Discussionmentioning

confidence: 99%

Bacterial defiance as a form of prodrug failure

2019

Preprint

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Classifying the mechanisms of antibiotic failure has led to the development of new treatment strategies for killing bacteria. Among the currently described mechanismswhich include resistance, persistence and tolerancewe propose defiance as a subclass of antibiotic failure specific to prodrugs. Using locked antimicrobial peptides (AMP) that are activated by bacterial 5 proteases as a prototypic prodrug, we observe that although treatment eliminates bacteria across the vast majority of environmental conditions (e.g., temperature, concentration of growth nutrients), bacteria spontaneously switch from susceptibility to defiance under conditions that alter the competing rates between bacterial proliferation and prodrug activation. To identify the determinants of this switch-like behavior, we model bacteria-prodrug dynamics as a multi-rate 10 feedback system and identify a dimensionless quantity we call the Bacterial Advantage Heuristic (BAH) that perfectly classifies bacteria as either defiant or susceptible across a broad range of treatment conditions. By recognizing that the bacterial switch from susceptibility to defiance behaves analogously to electronic transistors, we construct prodrug logic gates (e.g., AND, OR, NOT, etc.) to allow assembly of an integrated 3-bit multi-prodrug circuit that kills defiant bacteria 15 under all possible combinations of BAH values (i.e., 000, 001, …, 111) that represent a broad range of possible treatment conditions. Our study identifies a form of bacterial resistance specific to prodrugs that is described by a predictive dimensionless constant to reveal logic-based treatment strategies using multi-prodrug biological circuits.

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“…There has been some very significant development in this area in recent years. [124][125][126] One strategy that has been used for pretargeting delivery is the "click and release" reaction between an azido group and TCO. A cytotoxic drug can be caged in its inactive form, and activated by a reagent from a click-reaction pair such as azido-TCO, leading to drug release.…”

Section: Pretargeting Strategy-based Linkersmentioning

confidence: 99%

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Yang

Pan

Choudhury

et al. 2020

Medicinal Research Reviews

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Smart drugs, such as antibody-drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites. K E Y W O R D S antibody-drug conjugates, click and release, drug delivery, linker chemistry, targeted delivery, triggered release 1 | INTRODUCTION In the world of drug discovery and development, the concept of "smart drugs" broadly refers to those that can selectively affect disease-relevant target(s). However, to a certain degree, essentially all drugs are already selective toward the desired target(s) whether they are enzyme inhibitors, receptor ligands, ion channel blockers, inhibitors of protein-protein interaction, or even genotoxins used for cancer chemotherapy, among others. They would not have made through the various milestones of drug discovery and developmental processes if they were not sufficiently selective for the intended target(s). However, once administered into the human body, the highly complex living system often leads to many unexpected off-target effects. Thus, various additional approaches have been studied and

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Click and release: bioorthogonal approaches to “on-demand” activation of prodrugs

Abstract: This review summarizes recent developments in using bioorthogonal chemistry in prodrug design for the delivery of traditional small molecule- and gasotransmitter-based therapeutics.

Cited by 225 publications

References 112 publications

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

Bacterial defiance as a form of prodrug failure

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

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