| Autor: |
Elgaher WA; Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); and Pharmaceutical and Medicinal Chemistry, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany., Sharma KK; Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France., Haupenthal J; Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); and Pharmaceutical and Medicinal Chemistry, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany., Saladini F; Department of Medical Biotechnologies, University of Siena , Viale Mario Bracci 16, 53100 Siena, Italy., Pires M; Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France., Real E; Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France., Mély Y; Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France., Hartmann RW; Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); and Pharmaceutical and Medicinal Chemistry, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany. |
| Abstrakt: |
We 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. |
