Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus
ABSTRACTFoot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established ser...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2024-04-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.03372-23 |
| _version_ | 1797228850038439936 |
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| author | Yunjeong Kim Emma Pool Eunji Kim Chamandi S. Dampalla Harry Nhat Nguyen David K. Johnson Scott Lovell William C. Groutas Kyeong-Ok Chang |
| author_facet | Yunjeong Kim Emma Pool Eunji Kim Chamandi S. Dampalla Harry Nhat Nguyen David K. Johnson Scott Lovell William C. Groutas Kyeong-Ok Chang |
| author_sort | Yunjeong Kim |
| collection | DOAJ |
| description | ABSTRACTFoot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway.IMPORTANCEFood-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals. |
| first_indexed | 2024-04-24T15:03:14Z |
| format | Article |
| id | doaj.art-7ad3fe15365b43abbcf77691f2b8c7d8 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-24T15:03:14Z |
| publishDate | 2024-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-7ad3fe15365b43abbcf77691f2b8c7d82024-04-02T14:16:18ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972024-04-0112410.1128/spectrum.03372-23Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virusYunjeong Kim0Emma Pool1Eunji Kim2Chamandi S. Dampalla3Harry Nhat Nguyen4David K. Johnson5Scott Lovell6William C. Groutas7Kyeong-Ok Chang8Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USADepartment of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USADepartment of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USADepartment of Chemistry, Wichita State University, Wichita, Kansas, USADepartment of Chemistry, Wichita State University, Wichita, Kansas, USAComputational Chemical Biology Core, The University of Kansas, Lawrence, Kansas, USAProtein Structure and X-ray Crystallography Laboratory, The University of Kansas, Lawrence, Kansas, USADepartment of Chemistry, Wichita State University, Wichita, Kansas, USADepartment of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USAABSTRACTFoot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway.IMPORTANCEFood-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals.https://journals.asm.org/doi/10.1128/spectrum.03372-23food-and-mouth disease3C proteaseprotease inhibitorantiviralstructure-activity relationships |
| spellingShingle | Yunjeong Kim Emma Pool Eunji Kim Chamandi S. Dampalla Harry Nhat Nguyen David K. Johnson Scott Lovell William C. Groutas Kyeong-Ok Chang Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus Microbiology Spectrum food-and-mouth disease 3C protease protease inhibitor antiviral structure-activity relationships |
| title | Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus |
| title_full | Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus |
| title_fullStr | Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus |
| title_full_unstemmed | Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus |
| title_short | Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus |
| title_sort | potent small molecule inhibitors against the 3c protease of foot and mouth disease virus |
| topic | food-and-mouth disease 3C protease protease inhibitor antiviral structure-activity relationships |
| url | https://journals.asm.org/doi/10.1128/spectrum.03372-23 |
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