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dc.contributor.authorKamal, Ahmed Ashraf Moustafa
dc.contributor.authorHabib, Monica
dc.contributor.authorHaupenthal, Joerg
dc.contributor.authorHartmann, Rolf Wolfgang
dc.contributor.authorEmpting, Martin
dc.date.accessioned2019-10-29T10:43:18Z
dc.date.available2019-10-29T10:43:18Z
dc.date.issued2019-02-25
dc.identifier.citationBiol Chem. 2019 Feb 25;400(3):333-342. doi: 10.1515/hsz-2018-0333.en_US
dc.identifier.issn1437-4315
dc.identifier.pmid30657738
dc.identifier.doi10.1515/hsz-2018-0333
dc.identifier.urihttp://hdl.handle.net/10033/621994
dc.description.abstractRNA polymerase (RNAP) remains a relatively underexplored target with only rifampicin and fidaxomicin in clinical use. Hence, the concurrent rise in bacterial resistance rate urges the search for novel RNAP inhibitors with novel mode of action. In this work, we investigated the impact of several systematic modifications including sidechain-to-sidechain macrocylization in α-helical content and biological activity of a previously identified inhibitory sigma factor fragment. Ala-scan results, peptide truncation from both the N- and C- terminus, and modifications inspired by other RNAP inhibitors revealed novel structure activity relationships but did not yield a superior sequence. Additionally, four insertion points for non-natural amino acids bearing side chains required for macrocylization were explored. Linear precursors showed improved stabilization of α-helical content compared to the original sequence as demonstrated by CD spectroscopy. However, this increase in α-helicity did not translate into improved biological activity. Instead, complete abolishment of RNAP inhibitory activity occurred. We hypothesize three possible reasons for such discrepancy and offer basis for further optimization efforts for this peptidic RNAP inhibitor.en_US
dc.language.isoenen_US
dc.publisherDe Gruyteren_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectRNA polymeraseen_US
dc.subjectanti-infectiveen_US
dc.subjectclick chemistryen_US
dc.subjectmacrocyclic peptidesen_US
dc.subjectα-helixen_US
dc.titleHit evaluation of an α-helical peptide: Ala-scan, truncation and sidechain-to-sidechain macrocyclization of an RNA polymerase Inhibitor.en_US
dc.typeArticleen_US
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalBiological Chemistryen_US
dc.source.journaltitleBiological chemistry


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