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Novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo.
Abstract: Neurotropic alphaviruses, including western, eastern, and Venezuelan equine encephalitis viruses, cause serious and potentially fatal central nervous system infections in humans for which no currently approved therapies exist. We previously identified a series of thieno[3,2-b]pyrrole derivatives as novel inhibitors of neurotropic alphavirus replication, using a cell-based phenotypic assay (W. Peng et al., J. Infect. Dis. 199:950-957, 2009, doi:http://dx.doi.org/10.1086/597275), and subsequently developed second- and third-generation indole-2-carboxamide derivatives with improved potency, solubility, and metabolic stability (J. A. Sindac et al., J. Med. Chem. 55:3535-3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; J. A. Sindac et al., J. Med. Chem. 56:9222-9241, 2013, http://dx.doi.org/10.1021/jm401330r). In this report, we describe the antiviral activity of the most promising third-generation lead compound, CCG205432, and closely related analogs CCG206381 and CCG209023. These compounds have half-maximal inhibitory concentrations of ∼1 μM and selectivity indices of >100 in cell-based assays using western equine encephalitis virus replicons. Furthermore, CCG205432 retains similar potency against fully infectious virus in cultured human neuronal cells. These compounds show broad inhibitory activity against a range of RNA viruses in culture, including members of the Togaviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Although their exact molecular target remains unknown, mechanism-of-action studies reveal that these novel indole-based compounds target a host factor that modulates cap-dependent translation. Finally, we demonstrate that both CCG205432 and CCG209023 dampen clinical disease severity and enhance survival of mice given a lethal western equine encephalitis virus challenge. These studies demonstrate that indole-2-carboxamide compounds are viable candidates for continued preclinical development as inhibitors of neurotropic alphaviruses and, potentially, of other RNA viruses. IMPORTANCE There are currently no approved drugs to treat infections with alphaviruses. We previously identified a novel series of compounds with activity against these potentially devastating pathogens (J. A. Sindac et al., J. Med. Chem. 55:3535-3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; W. Peng et al., J. Infect. Dis. 199:950-957, 2009, doi:http://dx.doi.org/10.1086/597275; J. A. Sindac et al., J. Med. Chem. 56:9222-9241, 2013, http://dx.doi.org/10.1021/jm401330r). We have now produced third-generation compounds with enhanced potency, and this manuscript provides detailed information on the antiviral activity of these advanced-generation compounds, including activity in an animal model. The results of this study represent a notable achievement in the continued development of this novel class of antiviral inhibitors.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Publication Date: 2014-07-16 PubMed ID: 25031353PubMed Central: PMC4178776DOI: 10.1128/JVI.01671-14Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- N.I.H.
- Extramural
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research focuses on exploring the antiviral potential of indole-2-carboxamide compounds in combating neurotropic alphaviruses which cause serious central nervous system infections. The effective third-generation compound CCG205432 and its related analogs significantly reduced the severity of disease and improved survival rates in mice infected with western equine encephalitis virus.
Introduction and Background
- Alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses are known to cause severe and sometimes fatal infections in the central nervous system in humans.
- Currently, there are no approved therapies for such infections, necessitating the need for developing new effective treatments.
Previous Research and Development
- Prior to this research, the same team had identified a series of thieno[3,2-b]pyrrole derivatives as inhibitors inhibiting the replication of neurotropic alphaviruses.
- Later, they developed second- and third-generation indole-2-carboxamide derivatives aiming for improved potency, solubility, and metabolic stability.
Antiviral Activity of Indole-2-carboxamide Derivatives
- In the present study, the researchers further investigated the antiviral activity of the most promising third-generation lead compound, CCG205432, along with two closely related analogs CCG206381 and CCG209023.
- These compounds showed half-maximal inhibitory concentrations of about 1 μM and selectivity indices of over 100 in cell-based assays using western equine encephalitis virus replicons.
- Furthermore, CCG205432 maintained similar potency against the fully infectious virus in cultured human neuronal cells.
Activity Against Other Viruses
- These indole-2-carboxamide compounds displayed broad inhibitory activity against a range of RNA viruses in culture. This includes members from the Togaviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families.
- While the exact molecular target of these compounds is still unknown, the study findings suggest these indole-based compounds target a host factor that modulates cap-dependent translation.
In Vivo Efficacy
- The compounds, specifically CCG205432 and CCG209023, reduced the disease severity and improved survival rates in mice infected with a lethal dose of western equine encephalitis virus.
- The findings highlighted the potential of indole-2-carboxamide compounds as candidates for continued preclinical development as inhibitors of neurotropic alphaviruses and other RNA viruses.
Significance and Future Directions
- This research represents a significant contribution to the development of novel class of antiviral inhibitors.
- The detailed information on the antiviral activity of third-generation compounds in this study will be instrumental in further research targeting alphaviruses.
Cite This Article
APA
Delekta PC, Dobry CJ, Sindac JA, Barraza SJ, Blakely PK, Xiang J, Kirchhoff PD, Keep RF, Irani DN, Larsen SD, Miller DJ.
(2014).
Novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo.
J Virol, 88(19), 11199-11214.
https://doi.org/10.1128/JVI.01671-14 Publication
Researcher Affiliations
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan, USA milldavi@umich.edu.
MeSH Terms
- Animals
- Antiviral Agents / chemical synthesis
- Antiviral Agents / pharmacology
- Bunyaviridae / drug effects
- Bunyaviridae / growth & development
- Cell Line
- Encephalitis Virus, Western Equine / drug effects
- Encephalitis Virus, Western Equine / growth & development
- Encephalitis Virus, Western Equine / pathogenicity
- Encephalomyelitis, Equine / drug therapy
- Encephalomyelitis, Equine / mortality
- Encephalomyelitis, Equine / virology
- Female
- Indoles / chemical synthesis
- Indoles / pharmacology
- Inhibitory Concentration 50
- Mice
- Mice, Inbred C57BL
- Neurons / drug effects
- Neurons / virology
- Paramyxoviridae / drug effects
- Paramyxoviridae / growth & development
- Picornaviridae / drug effects
- Picornaviridae / growth & development
- Protein Biosynthesis / drug effects
- Pyridines / chemical synthesis
- Pyridines / pharmacology
- Replicon / drug effects
- Structure-Activity Relationship
- Survival Analysis
- Virus Replication / drug effects
Grant Funding
- R01 AI089417 / NIAID NIH HHS
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