Show simple item record

dc.contributor.authorElgaher, Walid A M
dc.contributor.authorSharma, Kamal K
dc.contributor.authorHaupenthal, Jörg
dc.contributor.authorSaladini, Francesco
dc.contributor.authorPires, Manuel
dc.contributor.authorReal, Eleonore
dc.contributor.authorMély, Yves
dc.contributor.authorHartmann, Rolf W
dc.date.accessioned2016-07-11T14:26:33Z
dc.date.available2016-07-11T14:26:33Z
dc.date.issued2016-07-07
dc.identifier.citationDiscovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors. 2016: J. Med. Chem.en
dc.identifier.issn1520-4804
dc.identifier.pmid27339173
dc.identifier.doi10.1021/acs.jmedchem.6b00730
dc.identifier.urihttp://hdl.handle.net/10033/615909
dc.description.abstractWe are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.
dc.languageENG
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleDiscovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalJournal of medicinal chemistryen
refterms.dateFOA2017-07-15T00:00:00Z
html.description.abstractWe are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.


Files in this item

Thumbnail
Name:
Elgaher et al.pdf
Size:
908.6Kb
Format:
PDF
Description:
original manuscript
Thumbnail
Name:
Supporting info.pdf
Size:
2.089Mb
Format:
PDF
Description:
supporting information

This item appears in the following Collection(s)

Show simple item record

http://creativecommons.org/licenses/by-nc-sa/4.0/
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/