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dc.contributor.authorGall, Flavio-
dc.contributor.authorHohl, Deborah-
dc.contributor.authorFrasson, David-
dc.contributor.authorWermelinger, Tobias-
dc.contributor.authorMittl, Peer R. E.-
dc.contributor.authorSievers, Martin-
dc.contributor.authorRiedl, Rainer-
dc.date.accessioned2021-02-18T10:43:18Z-
dc.date.available2021-02-18T10:43:18Z-
dc.date.issued2019-01-07-
dc.identifier.issn1433-7851de_CH
dc.identifier.issn1521-3773de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/21751-
dc.description.abstractDe 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).de_CH
dc.language.isoende_CH
dc.publisherWileyde_CH
dc.relation.ispartofAngewandte Chemie: International Editionde_CH
dc.rightsLicence according to publishing contractde_CH
dc.subjectDrug designde_CH
dc.subjectMedicinal chemistryde_CH
dc.subjectPeptidomimeticsde_CH
dc.subjectStructural biologyde_CH
dc.subjectStructure-activity relationshipde_CH
dc.subjectBinding sitesde_CH
dc.subjectCrystallographyde_CH
dc.subjectCyclizationde_CH
dc.subjectMatrix metalloproteinase 13de_CH
dc.subjectMatrix metalloproteinase inhibitorsde_CH
dc.subjectMolecular dynamics simulationde_CH
dc.subjectCyclic peptidesde_CH
dc.subjectPeptidomimeticsde_CH
dc.subjectProtease inhibitorsde_CH
dc.subjectTissue inhibitor of metalloproteinasesde_CH
dc.subjectX-Rayde_CH
dc.subject.ddc615: Pharmakologie und Therapeutikde_CH
dc.titleDrug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor templatede_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
zhaw.organisationalunitInstitut für Chemie und Biotechnologie (ICBT)de_CH
dc.identifier.doi10.1002/anie.201812348de_CH
dc.identifier.pmid30615822de_CH
zhaw.funding.euNode_CH
zhaw.issue12de_CH
zhaw.originated.zhawYesde_CH
zhaw.pages.end4055de_CH
zhaw.pages.start4051de_CH
zhaw.publication.statuspublishedVersionde_CH
zhaw.volume58de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
zhaw.author.additionalNode_CH
zhaw.display.portraitYesde_CH
Appears in collections:Publikationen Life Sciences und Facility Management

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