| Publikationstyp: | Beitrag in wissenschaftlicher Zeitschrift |
| Art der Begutachtung: | Peer review (Publikation) |
| Titel: | Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template |
| Autor/-in: | Gall, Flavio Hohl, Deborah Frasson, David Wermelinger, Tobias Mittl, Peer R. E. Sievers, Martin Riedl, Rainer |
| et. al: | No |
| DOI: | 10.1002/anie.201812348 |
| Erschienen in: | Angewandte Chemie: International Edition |
| Band(Heft): | 58 |
| Heft: | 12 |
| Seite(n): | 4051 |
| Seiten bis: | 4055 |
| Erscheinungsdatum: | 7-Jan-2019 |
| Verlag / Hrsg. Institution: | Wiley |
| ISSN: | 1433-7851 1521-3773 |
| Sprache: | Englisch |
| Schlagwörter: | Drug design; Medicinal chemistry; Peptidomimetics; Structural biology; Structure-activity relationship; Binding sites; Crystallography; Cyclization; Matrix metalloproteinase 13; Matrix metalloproteinase inhibitors; Molecular dynamics simulation; Cyclic peptides; Peptidomimetics; Protease inhibitors; Tissue inhibitor of metalloproteinases; X-Ray |
| Fachgebiet (DDC): | 615: Pharmakologie und Therapeutik |
| Zusammenfassung: | De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50 : 170 nm) and MMP-9 (IC50 : 140 nm). |
| URI: | https://digitalcollection.zhaw.ch/handle/11475/21751 |
| Volltext Version: | Publizierte Version |
| Lizenz (gemäss Verlagsvertrag): | Lizenz gemäss Verlagsvertrag |
| Departement: | Life Sciences und Facility Management |
| Organisationseinheit: | Institut für Chemie und Biotechnologie (ICBT) |
| Enthalten in den Sammlungen: | Publikationen Life Sciences und Facility Management |
Dateien zu dieser Ressource:
Es gibt keine Dateien zu dieser Ressource.
Zur Langanzeige
Gall, F., Hohl, D., Frasson, D., Wermelinger, T., Mittl, P. R. E., Sievers, M., & Riedl, R. (2019). Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template. Angewandte Chemie: International Edition, 58(12), 4051–4055. https://doi.org/10.1002/anie.201812348
Gall, F. et al. (2019) ‘Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template’, Angewandte Chemie: International Edition, 58(12), pp. 4051–4055. Available at: https://doi.org/10.1002/anie.201812348.
F. Gall et al., “Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template,” Angewandte Chemie: International Edition, vol. 58, no. 12, pp. 4051–4055, Jan. 2019, doi: 10.1002/anie.201812348.
GALL, Flavio, Deborah HOHL, David FRASSON, Tobias WERMELINGER, Peer R. E. MITTL, Martin SIEVERS und Rainer RIEDL, 2019. Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template. Angewandte Chemie: International Edition. 7 Januar 2019. Bd. 58, Nr. 12, S. 4051–4055. DOI 10.1002/anie.201812348
Gall, Flavio, Deborah Hohl, David Frasson, Tobias Wermelinger, Peer R. E. Mittl, Martin Sievers, and Rainer Riedl. 2019. “Drug Design Inspired by Nature : Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template.” Angewandte Chemie: International Edition 58 (12): 4051–55. https://doi.org/10.1002/anie.201812348.
Gall, Flavio, et al. “Drug Design Inspired by Nature : Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template.” Angewandte Chemie: International Edition, vol. 58, no. 12, Jan. 2019, pp. 4051–55, https://doi.org/10.1002/anie.201812348.
Alle Ressourcen in diesem Repository sind urheberrechtlich geschützt, soweit nicht anderweitig angezeigt.