title: Anti-infective Activity of 2-Cyano-3-Acrylamide Inhibitors with Improved Drug-Like Properties against Two Intracellular Pathogens.
abstract: Due to the rise of antibiotic resistance and the small number of effective antiviral drugs, new approaches for treating infectious diseases are urgently needed. Identifying targets for host-based therapies represents an emerging strategy for drug discovery. The ubiquitin-proteasome system is a central mode of signaling in the eukaryotic cell and may be a promising target for therapies that bolster the host's ability to control infection. Deubiquitinase (DUB) enzymes are key regulators of the host inflammatory response, and we previously demonstrated that a selective DUB inhibitor and its derivative promote anti-infective activities in host cells. To find compounds with anti-infective efficacy but improved toxicity profiles, we tested a library of predominantly 2-cyano-3-acrylamide small-molecule DUB inhibitors for anti-infective activity in macrophages against two intracellular pathogens: murine norovirus (MNV) and Listeria monocytogenes We identified compound C6, which inhibited DUB activity in human and murine cells and reduced intracellular replication of both pathogens with minimal toxicity in cell culture. Treatment with C6 did not significantly affect the ability of macrophages to internalize virus, suggesting that the anti-infective activity interferes with postentry stages of the MNV life cycle. Metabolic stability and pharmacokinetic assays showed that C6 has a half-life in mouse liver microsomes of ∼20 min and has a half-life of approximately 4 h in mice when administered intravenously. Our results provide a framework for targeting the host ubiquitin system in the development of host-based therapies for infectious disease. Compound C6 represents a promising tool with which to elucidate the role of DUBs in the macrophage response to infection.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Karla D
authors.initials: KD
authors.lastname: Passalacqua
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Charbonneau
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
authors.affiliation: Vahlteich Medicinal Chemistry Core, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Hollis D
authors.initials: HD
authors.lastname: Showalter
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Hanshi
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA cwobus@umich.edu oriordan@umich.edu.
authors.forename: Mary X D
authors.initials: MX
authors.lastname: O'Riordan
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA cwobus@umich.edu oriordan@umich.edu.
authors.forename: Christiane E
authors.identifier: 0000-0001-5286-0924
authors.initials: CE
authors.lastname: Wobus
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D000072017:Deubiquitinating Enzymes / Q000378:metabolism; D006801:Humans; D008089:Listeria monocytogenes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000821:virology; D051379:Mice; D029322:Norovirus / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D000072017:Deubiquitinating Enzymes