Chemical derivatives of a small molecule deubiquitinase inhibitor have antiviral activity against several RNA viruses.
Most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. A good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. The small molecule WP1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other RNA viruses. In this study, we screened a library of 31 small molecule derivatives of WP1130 to identify compounds that retained the broad-spectrum antiviral activity of the parent compound in vitro but exhibited improved drug-like properties, particularly increased aqueous solubility. Seventeen compounds significantly reduced murine norovirus infection in murine macrophage RAW 264.7 cells, with four causing decreases in viral titers that were similar or slightly better than WP1130 (1.9 to 2.6 log scale). Antiviral activity was observed following pre-treatment and up to 1 hour postinfection in RAW 264.7 cells as well as in primary bone marrow-derived macrophages. Treatment of the human norovirus replicon system cell line with the same four compounds also decreased levels of Norwalk virus RNA. No significant cytotoxicity was observed at the working concentration of 5 µM for all compounds tested. In addition, the WP1130 derivatives maintained their broad-spectrum antiviral activity against other RNA viruses, Sindbis virus, LaCrosse virus, encephalomyocarditis virus, and Tulane virus. Thus, altering structural characteristics of WP1130 can maintain effective broad-spectrum antiviral activity while increasing aqueous solubility.
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
Marta J
MJ
Gonzalez-Hernandez
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Anupama
A
Pal
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
Kofi E
KE
Gyan
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
Marie-Eve
ME
Charbonneau
Vahlteich Medicinal Chemistry Core, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, United States of America.
Hollis D
HD
Showalter
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Nicholas J
NJ
Donato
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
Mary
M
O'Riordan
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
Christiane E
CE
Wobus
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003487:Cyanoacrylates; D004686:Encephalomyocarditis virus / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054884:Host-Pathogen Interactions; D006801:Humans; D018062:La Crosse virus / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D051379:Mice; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D029322:Norovirus / Q000187:drug effects / Q000502:physiology; D009663:Norwalk virus / Q000187:drug effects / Q000502:physiology; D061251:Primary Cell Culture; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012845:Sindbis Virus / Q000187:drug effects / Q000502:physiology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D003487:Cyanoacrylates; D004791:Enzyme Inhibitors; D009570:Nitriles; D011725:Pyridines; D054852:Small Molecule Libraries; C519751:degrasyn; D064570:Ubiquitin-Specific Proteases