1. The imidazopyrrolopyridine analogue AG110 is a novel, highly selective inhibitor of pestiviruses that targets the viral RNA-dependent RNA polymerase at a hot spot for inhibition of viral repliation
- Author
-
Pieter Leyssen, Alain Gueiffier, Tong Li, Olivier Chavignon, Hélène Dutartre, Harald Mittendorfer, Johan Neyts, Erik De Clercq, Jean-Claude Teulade, Bruno Canard, Jan Paeshuyse, Carine Letellier, Pierre Kerkhofs, Piet Herdewijn, Matheus Froeyen, Jean-Michel Chezal, Gerhard Puerstinger, Frank Koenen, Robert Vrancken, Department of Microbiology and Immunology, Rega Institute for Medical Research, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratory of Medicinal Chemistry, Rega Institute-Catholic University of Leuven, Rega Institute for Medical Research [Leuven, België], Oncogenèse rétrovirale – Retroviral Oncogenesis (OR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Department of Virology, Veterinary and Agrochemical Research Centre (VAR-CODA-CERVA), University of Trento [Trento], Laboratory for Medicinal Chemistry, Université de Tours (UT), Etude Métabolique des Molécules Marquées, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Thérapie Vectorisée (IMTV), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cancéropôle CLARA-ITMO ' Technologies pour la Santé ', Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Rega Institute for Medical Research, Oncogenèse rétrovirale – Retroviral Oncogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Tours, ITMO ' Technologies pour la Santé '-Cancéropôle CLARA-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)
- Subjects
Models, Molecular ,Hepatitis C virus ,viruses ,Immunology ,Mutant ,RNA-dependent RNA polymerase ,Virus Replication ,medicine.disease_cause ,Antiviral Agents ,Microbiology ,Virus ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Virology ,RNA polymerase ,Vaccines and Antiviral Agents ,medicine ,Animals ,Enzyme Inhibitors ,Binding site ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Diarrhea Viruses, Bovine Viral ,biology ,030306 microbiology ,Pestivirus ,Pestivirus Infections ,RNA-Dependent RNA Polymerase ,biology.organism_classification ,Molecular biology ,3. Good health ,chemistry ,Viral replication ,Insect Science ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Pyrazoles ,Cattle - Abstract
Ethyl 2-methylimidazo[1,2- a ]pyrrolo[2,3- c ]pyridin-8-carboxylate (AG110) was identified as a potent inhibitor of pestivirus replication. The 50% effective concentration values for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect, viral RNA synthesis, and production of infectious virus were 1.2 ± 0.5 μM, 5 ± 1 μM, and 2.3 ± 0.3 μM, respectively. AG110 proved inactive against the hepatitis C virus and a flavivirus. AG110 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carry the E291G mutation in the viral RNA-dependent RNA polymerase (RdRp). AG110-resistant virus is cross-resistant to the cyclic urea compound 1453 which also selects for the E291G drug resistance mutation. Moreover, BVDV that carries the F224S mutation (because of resistance to the imidazopyridine 5-[(4-bromophenyl)methyl]-2-phenyl-5 H -imidazo[4,5- c ]pyridine [BPIP]and VP32947) is also resistant to AG110. AG110 did not inhibit the in vitro activity of recombinant BVDV RdRp but inhibited the activity of BVDV replication complexes (RCs). Molecular modeling revealed that E291 is located in a small cavity near the tip of the finger domain of the RdRp about 7 Å away from F224. Docking of AG110 in the crystal structure of the BVDV RdRp revealed several potential contacts including with Y257. The E291G mutation might enable the free rotation of Y257, which might in turn destabilize the backbone of the loop formed by residues 223 to 226, rendering more mobility to F224 and, hence, reducing the affinity for BPIP and VP32947. It is concluded that a single drug-binding pocket exists within the finger domain region of the BVDV RdRp that consists of two separate but potentially overlapping binding sites rather than two distinct drug-binding pockets.
- Published
- 2007
- Full Text
- View/download PDF