Drug Design Inspired by Nature: Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template

Gall, Flavio M.; Hohl, Deborah; Frasson, David; Wermelinger, Tobias; Mittl, Peer R. E.; Sievers, Martin; Riedl, Rainer

doi:10.1002/anie.201812348

Cited by 14 publications

(22 citation statements)

References 49 publications

(94 reference statements)

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“…These polypharmacology approaches have been applied very successfully for other target classes and appear to be a clear continuation of drug‐discovery approaches toward clinical MMP inhibitors. Recently, a potent and selective cyclic membrane‐permeable TIMP peptidomimetic targeting MMP‐2, ‐9, and ‐13 suitable for polypharmacology approaches has been disclosed . Due to impressive progress through diverse strategies to modulate MMP activity, ranging from small‐molecule inhibitors to biopharmaceuticals, the probability of developing drugs for the clinical treatment of MMP‐related diseases has been tremendously increased.…”

Section: Discussionmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

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Section: Discussionmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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“…Additionally, this serendipitously trapped product complex may provide yet another starting point from which active site-targeted mirolysin inhibitors might be developed. A similar serendipitous discovery of a product fragment captured in a crystal structure of MMP-13 recently led to the design of a potent peptidomimetic inhibitor of this metalloprotease (Gall et al, 2019). Together the new structures of mirolysin reported here offer a window from which to understand the function of this protease in gum disease, with a glimpse of how one might inhibit this intriguing target.…”

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confidence: 72%

Mirolysin structures open a window on gum disease

Radisky

2020

IUCrJ

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Periodontitis, commonly known as gum disease, is a chronic inflammatory disease characterized by dysregulation of the oral microbiota in the subgingival space below the gum line (Hajishengallis, 2015). Healthy gums are compromised by a proliferation of pathogenic anaerobic bacteria, most commonly the triad of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia. These pathogens release 'virulence factors', molecules that aid their colonization and survival in the subgingival niche and their evasion of the host immune response. Synergistic interactions of the pathogenic microbes with normal oral microbiota lead to a sustained host inflammatory response, degrading periodontal tissues, eroding bone, and ultimately leading to tooth loss. Severe periodontitis affects around 10% of the human population, and health implications are not limited to oral health; the chronic inflammatory conditions precipitated by the disease can extend to systemic manifestations, contributing to risk of cardiovascular and respiratory diseases, diabetes, rheumatoid arthritis, and cancer (Hajishengallis, 2015; Peters et al., 2017). Proteases are amongst the most abundant virulence factors produced by periodontal pathogens. These enzymes degrade host proteins to feed bacterial growth, and also serve as key mediators of immune-subversive mechanisms, for example by degrading or inactivating endogenous antimicrobial peptides and components of the host complement system (Hajishengallis, 2015). One of the proteases implicated in these activities is mirolysin, a metalloprotease secreted by T. forsythia. Mirolysin cleaves multiple components of the complement pathway to protect the pathogen against complementmediated killing, and degrades the antimicrobial peptide LL-37, a human host defense peptide secreted by epithelial and immune cells at sites of infection (Jusko et al., 2015; Koneru et al., 2017). As a recently discovered mediator of T. forsythia survival and immune evasion, mirolysin offers a potential therapeutic target, yet until now the structural basis for its latency, activation and substrate specificity have not been defined. In this issue of IUCrJ, Guevara, Rodriguez-Banqueri et al. report high-resolution crystal structures of promirolysin, defining the mechanism of latency of the precursor protein (Guevara et al., 2020). Like nearly all proteases, mirolysin is first produced as a zymogen, maintained in an inactive state by the presence of an N-terminal extension known as a pro-peptide, pro-segment or pro-domain (Fig. 1). Upon proteolytic cleavage of the pro-segment, the active site of a protease becomes exposed and accessible to substrates. While unified by this common theme, different clans and families of metalloproteases show myriad variations in the details of how latency is maintained and activation subsequently achieved. These variations have been carefully cataloged in over 60 crystal structures of metalloprotease zymogens, including many from the Gomis-Rü th research group (Arolas et al., 2018). Here, the grou...

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“…We use CyBy 2 intensively as the central data processing tool in our research group. In recent years, it has proven its value for the design, synthesis and analysis of our drug molecules in complex medicinal chemistry projects [45–50].…”

Section: Resultsmentioning

confidence: 99%

CyBy2: a strongly typed, purely functional framework for chemical data management

Höck

Riedl

2019

J Cheminform

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We present the development of CyBy2, a versatile framework for chemical data management written in purely functional style in Scala, a modern multi-paradigm programming language. Together with the core libraries we provide a fully functional example implementation of a HTTP server together with a single page web client with powerful querying and visualization capabilities, providing essential functionality for people working in the field of organic and medicinal chemistry. The main focus of CyBy2 are the diverse needs of different research groups in the field and therefore the flexibility required from the underlying data model. Techniques for writing type level specifications giving strong guarantees about the correctness of the implementation are described, together with the resulting gain in confidence during refactoring. Finally we talk about the advantages of using a single code base from which the server, the client and the software’s documentation pages are being generated. We conclude with a comparison with existing open source solutions. All code described in this article is published under version 3 of the GNU General Public License and available from GitHub including an example implementation of both backend and frontend together with documentation how to download and compile the software (available at https://github.com/stefan-hoeck/cyby2).

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Drug Design Inspired by Nature: Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template

Abstract: Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Cited by 14 publications

References 49 publications

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Mirolysin structures open a window on gum disease

CyBy2: a strongly typed, purely functional framework for chemical data management

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