The development of matrix-metalloproteinase responsive sensors for the machine-independent detection of oral inflammation

Mors, Björn Ter; Drießen, Marc D.; Seher, Axel; Haubitz, Imme; Raschig, Martina; Nowak, Magdalena; Jockel‐Schneider, Yvonne; Linz, Christian; Meinel, Lorenz

doi:10.1039/d3sd00031a

Cited by 3 publications

(5 citation statements)

References 42 publications

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“…(7) The lowest, (8) ...the highest value included in the cumulative score, and (9) ...the median of the eight values. (10) The normalized score.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…It thereby offers guidance for testing a broad range of other target proteases. For example, we have recently described sensors for the detection of oral inflammation, where we followed the same general steps …”

Section: Discussionmentioning

confidence: 99%

“…The development of a peptide sequence that is specifically cut by a protease can serve multiple intentions. As part of bioconjugates, cleavable linkers in general are used to reduce steric hindrance, enhance bioactivity, and enable controlled or targeted drug release or separate metabolism of the disassembled domains after cleavage. − The use of P rotease s ensitive l inkers (PSLs) as such cleavable moieties induces the ability to selectively respond to the local proteolytic environment.…”

Section: Introductionmentioning

confidence: 99%

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An Introductory Guide to Protease Sensitive Linker Design Using Matrix Metalloproteinase 13 as an Example

Hamm,

Meinel,

Driessen

2024

ACS Biomater. Sci. Eng.

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Proteases play a crucial role, not only in physiological, but also in pathological processes, such as cancer, inflammation, arthritis, Alzheimer's, and infections, to name but a few. Their ability to cleave peptides can be harnessed for a broad range of biotechnological purposes. To do this efficiently, it is essential to find an amino acid sequence that meets the necessary requirements, including interdependent factors like specificity, selectivity, cleavage kinetics, or synthetic accessibility. Cleavage sequences from natural substrates of the protease may not be optimal in terms of specificity and selectivity, which is why these frequently require arduous and sometimes unsuccessful optimization such as by iterative exchange of single amino acids. Hence, here we describe the systematic design of protease sensitive linkers (PSLs)�peptide sequences specifically cleaved by a target protease�guided by the mass spectrometry based determination of target protease specific cleavage sites from a proteome-based peptide library. It includes a procedure for identifying bespoke PSL sequences, their optimization, synthesis, and validation and introduces a program that can indicate potential cleavage sites by hundreds of enzymes in any arbitrary amino acid sequence. Thereby, we provide an introduction to PSL design, illustrated by the example of matrix metalloproteinase 13 (MMP13). This introduction can serve as a guide and help to greatly accelerate the development and use of protease-sensitive linkers in diverse applications.

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“…(7) The lowest, (8) ...the highest value included in the cumulative score, and (9) ...the median of the eight values. (10) The normalized score.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Introductory Guide to Protease Sensitive Linker Design Using Matrix Metalloproteinase 13 as an Example

Hamm,

Meinel,

Driessen

2024

ACS Biomater. Sci. Eng.

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“…We previously characterized selectivity of the PSL after proteolytic digest of MMPs 1, 8, 9 and 13. , All changes are located in the random coiled region of the N-terminus of FGF-2 (Figure B). 8-TAG-PSL-FGF was expressed using Escherichia coli (E.…”

Section: Resultsmentioning

confidence: 99%

“…The issue of tissue redistribution remains open and should be addressed by further modifications involving screening of novel plasma stabilized PSLs as demonstrated previously. 60 We are currently developing this strategy for presented 8(TAG)-PSL-FGF-2.…”

Section: ■ Conclusionmentioning

confidence: 99%

Matrix Metalloproteinase-Responsive Delivery of PEGylated Fibroblast Growth Factor 2

Gutmann,

Reinhardt,

Seidensticker

et al. 2023

ACS Biomater. Sci. Eng.

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Attachment of polyethylene glycol (PEG) chains is a common, wellstudied, and Food and Drug Administration-approved method to address the pharmacokinetic challenges of therapeutic proteins. Occasionally, PEGylation impairs the activity of pharmacodynamics (PD). To overcome this problem, disease-relevant cleavable linkers between the polymer and the therapeutic protein can unleash full PD by de-PEGylating the protein at its target site. In this study, we engineered a matrix metalloproteinase (MMP)-responsive fibroblast growth factor 2 (FGF-2) mutant that was site-specifically extended with a PEG polymer chain. Using bioinspired strategies, the bioconjugate was designed to release the native protein at the desired structure/ environment with preservation of the proliferative capacity in vitro on NIH3T3 cells. In vivo, hepatic exposure was diminished but not its renal distribution over time compared to unconjugated FGF-2. By releasing the growth factor from the PEG polymer in response to MMP cleavage, restored FGF-2 may enter hard-to-reach tissues and activate cell surface receptors or nuclear targets.

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Visually distinguishing between tumor tissue and healthy tissue within ten minutes using proteolytic probes

Reinhardt,

ter Mors,

Driessen

et al. 2024

Sens. Diagn.

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The development of matrix-metalloproteinase responsive sensors for the machine-independent detection of oral inflammation

Abstract: Periodontitis is a chronic inflammatory disease that affects an estimated 20–50% of the world's population and can lead to high follow-up costs for the healthcare system.

Cited by 3 publications

References 42 publications

An Introductory Guide to Protease Sensitive Linker Design Using Matrix Metalloproteinase 13 as an Example

An Introductory Guide to Protease Sensitive Linker Design Using Matrix Metalloproteinase 13 as an Example

Matrix Metalloproteinase-Responsive Delivery of PEGylated Fibroblast Growth Factor 2

Visually distinguishing between tumor tissue and healthy tissue within ten minutes using proteolytic probes

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