Synergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems

Yao, Qingxin; Feng, Lin; Fan, Xinyuan; Wang, Yiguang; Liu, Ye; Liu, Zhaofei; Jiang, Xingyu; Chen, Peng R.; Gao, Yuan

doi:10.1038/s41467-018-07490-6

Cited by 177 publications

(110 citation statements)

References 35 publications

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“…Our current study provides a thorough understanding of the catalytic mechanism of thermolysin, in particular, a new methodology for bottom-up nanofabrication of future soft-gel materials, and has instructive significance on the regulation of peptide sequences, secondary structure, morphology, and mechanical property of self-assembled hydrogels with precise design and control in molecular level by thermolysin and functional applications of peptide materials. [49][50][51][52][53][54]…”

Section: Resultsmentioning

confidence: 99%

Role of Thermolysin in Catalytic-Controlled Self-Assembly of Fmoc-Dipeptides

et al. 2020

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In recent years, short peptide self-assembled materials, prepared under the control of the thermolysin catalyst, have been investigated extensively and shown to acquire various morphologies and functions as building blocks for a wide range of biomaterials and device applications. However, the role played by thermolysin in this enzymatically triggered peptide self-assembly is still ambiguous. Herein, we designed a series of Fmoc-dipeptide amphiphiles to explore the catalytic role of thermolysin. The results from our experiments and computational simulations showed that hydrophobicity and amino acid sequences of substrates have a significant correlation with thermolysin actions, including the binding capacity and catalytic efficiency. Specifically, thermolysin favors a specific substrate pattern with a hydrophilic amino acid in the first residue and hydrophobic amino acid in the second residue. Moreover, thermolysin catalyzed reactions are bidirectional and could move toward hydrolysis or condensation based on the design of its diverse substrates (peptides). However, the specificity of the enzyme action lies in the major site of its cleavage, which is the terminal hydrophobic or bulky amino side chains. We designed a two-step reaction, taking advantage of the bidirectional catalytic actions of thermolysin, to modify the sequence of N α-fluorenylmethoxycarbonyl (Fmoc)-dipeptide from Fmoc-YL-COOH to Fmoc-YY-NH 2 and treated with thermolysin, which resulted in the enzyme-catalyzed gel-sol-gel transition. This work has an instructive significance in the regulation of peptide sequences, secondary amino acid structures, morphology, and the mechanical property of self-assembled hydrogels with precise design and control at the molecular level via thermolysin catalysis.

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Section: Resultsmentioning

confidence: 99%

Role of Thermolysin in Catalytic-Controlled Self-Assembly of Fmoc-Dipeptides

et al. 2020

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“…It is also worth noting that some very interesting work in developing new bioorthogonal reactions has been reported. [147][148][149][150] Though these new reactions may not have been used in targeted drug delivery, they offer additional opportunities in this area of research. We hope that the publication of this review will provide researchers a good reference for choosing a suitable chemical linker and chemical strategies for their prodrug design, and more importantly will stimulate more research into overcoming obstacles that this field still faces in developing smart drugs for clinical applications.…”

Section: Discussionmentioning

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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“…[20][21][22] These reversible, controllable, and dynamic noncovalent interactions allow these self-assembled systems of biomolecules to adapt well to the physiological environment to fully optimize their biological functions. [23][24][25][26] For example, the specic interaction among macromolecules causes a conformational change in the partner macromolecule to activate one of the binding partners to trigger a biological cascade. 27 In particular, low molecular weight peptides exhibit outstanding advantages (such as inherent biocompatibility, potential biodegradability, structural programmability, and easy preparation) compared to other existing self-assembly motifs.…”

Section: Introductionmentioning

confidence: 99%