Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

Wang, Chao; Díez, Juan J.; Park, HaJeung; Becker‐Pauly, Christoph; Fields, Gregg B.; Spicer, Timothy; Scampavia, Louis; Minond, Dmitriy; Bannister, Thomas D.

doi:10.20944/preprints202012.0354.v1

Cited by 4 publications

(5 citation statements)

References 16 publications

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“…The platform can also be utilised for libraries of any size; smaller, rationally selected libraries can be screened rapidly (e.g., analogues from a medicinal chemistry campaign) and progressed directly to secondary EC 50 screening, whilst the scalability of this platform makes it equally applicable to larger, more diverse libraries such as the ReFRAME collection (12,000 small molecules which have reached clinical development or undergone significant preclinical development (Janes et al, 2018)) and AstraZeneca's open innovation programme (AstraZeneca, 2022). Furthermore, it is feasible this HTS could be scaled up further based on the precedence for ultra-HTS discovery programmes which use the same fluorescent substrate (Madoux et al, 2016;Hou et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The SVMP assay implemented here has previously been used for quantifying venom activity and toxin inhibition and is based on the adapted use of a commercial assay designed for human MMPs (Albulescu et al, 2020b;Hou et al, 2021;Menzies et al, 2022;Nguyen et al, 2022). The fluorescence-quenched peptide substrate measures the activity of peptidases such as SVMPs which cleave the amide bond between the fluorescent group and the quencher group, resulting in an increase in fluorescence.…”

Section: Optimisation For High-throughput Capabilitymentioning

confidence: 99%

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Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors

Clare,

Dawson,

Westhorpe

et al. 2024

Front. Pharmacol.

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Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)—a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar EC50s comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.

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Section: Discussionmentioning

confidence: 99%

Section: Optimisation For High-throughput Capabilitymentioning

confidence: 99%

Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors

Clare,

Dawson,

Westhorpe

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…The SVMP assay implemented here has previously been used for quantifying venom activity and toxin inhibition and is based on the adapted use of a commercial assay designed for human MMPs (Albulescu et al, 2020b;Hou et al, 2021;Nguyen et al, 2022). The fluorescence-quenched peptide substrate measures the activity of peptidases such as SVMPs which cleave the amide bond between the fluorescent group and the quencher group, resulting in an increase in fluorescence.…”

Section: Optimisation For High-throughput Capabilitymentioning

confidence: 99%

Experimental and computational aspects of bioactive proteins from animal venoms: An insight into pharmacological properties and drug discovery

2024

Frontiers Research Topics

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Frontiers is more than just an open access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers journal seriesThe Frontiers journal series is a multi-tier and interdisciplinary set of openaccess, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. At the same time, the Frontiers journal series operates on a revolutionary invention, the tiered publishing system, initially addressing specific communities of scholars, and gradually climbing up to broader public understanding, thus serving the interests of the lay society, too. Dedication to qualityEach Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interactions between authors and review editors, who include some of the world's best academicians. Research must be certified by peers before entering a stream of knowledge that may eventually reach the public -and shape society; therefore, Frontiers only applies the most rigorous and unbiased reviews. Frontiers revolutionizes research publishing by freely delivering the most outstanding research, evaluated with no bias from both the academic and social point of view. By applying the most advanced information technologies, Frontiers is catapulting scholarly publishing into a new generation. What are Frontiers Research Topics?Frontiers Research Topics are very popular trademarks of the Frontiers journals series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area.

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“…7a,b & 8a,b), respectively. [36][37][38] The latter monocyclic or fused heteroaromatic derivatives represent the most potent inhibitors of meprins that have been reported to date, even without any functionalization of the actual diaryl-heteroaromatic scaffold.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure-Activity Relationships of Pyrazole-based Inhibitors of Meprin α and β

Tan

Jäger

Geissler

et al. 2022

Preprint

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Targeting metalloproteinases has been in focus of drug design for a long time. However, human proteinases of the astacin family, in particular meprin α and β emerged as potential drug targets just recently. More and more data links them to several diseases with different pathological background. Nevertheless, the validation of meprins as suitable drug targets requires highly potent and selective inhibitors as chemical probes to elucidate their role in pathophysiology. Albeit highly selective inhibitors of meprin β have already been reported, only inhibitors of meprin α with modest activity or selectivity are known. Starting from recently reported heteroaromatic scaffolds, the aim of this study was the optimization of meprin α and/or meprin β inhibition while keeping the favorable off-target inhibition profile over other metalloproteases. We now report novel potent pan-meprin inhibitors as well as highly active inhibitors of meprin α with superior selectivity over meprin β. The latter are suitable to serve as chemical probes and enable further target validation of meprin proteases.

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Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

Cited by 4 publications

References 16 publications

Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors

Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors

Experimental and computational aspects of bioactive proteins from animal venoms: An insight into pharmacological properties and drug discovery

Synthesis and Structure-Activity Relationships of Pyrazole-based Inhibitors of Meprin α and β

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