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Abstract
Canine distemper virus (CDV), a close relative of the human pathogen measles virus (MeV), is an enveloped, negative sense RNA virus that belongs to the genus Morbillivirus and causes severe diseases in dogs and other carnivores. Although the vaccination is available as a preventive measure against the disease, the occasional vaccination failure highlights the importance of therapeutic alternatives such as antivirals against CDV. The morbilliviral cell entry system relies on two interacting envelope glycoproteins: the attachment (H) and fusion (F) proteins. Here, to potentially discover novel entry inhibitors targeting CDV H, F and/or the cognate receptor: signaling lymphocyte activation molecule (SLAM) proteins, we designed a quantitative cell-based fusion assay that matched high-throughput screening (HTS) settings. By screening two libraries of small molecule compounds, we successfully identified two membrane fusion inhibitors (F2736-3056 and F2261-0043). Although both inhibitors exhibited similarities in structure and potency with the small molecule compound 3G (an AS-48 class morbilliviral F-protein inhibitor), F2736-3056 displayed improved efficacy in blocking fusion activity when a 3G-escape variant was employed. Altogether, we present a cell-based fusion assay that can be utilized not only to discover antiviral agents against CDV but also to dissect the mechanism of morbilliviral-mediated cell-binding and cell-to-cell fusion activity.
Highlights
Canine distemper is a highly infectious disease caused by the canine distemper virus (CDV), a member of the family Paramyxoviridae and closely related to the measles virus (MeV) human pathogen
CDV establishes the infection by binding a receptor: signaling lymphocyte activation molecule family member 1 (SLAM/F1, or CD150), expressed by dendritic cells (DCs), subsets of thymocytes, macrophages, and T- and B-lymphocytes [7,8]
Provided that previous screens involving reporter protein-expressing recombinant live-viruses resulted in the discovery of anti-F or anti-L inhibitors [24], we investigated the possibility to increase the chances to identify novel antivirals by designing a more viral protein-targeted bioassay
Summary
Canine distemper is a highly infectious disease caused by the canine distemper virus (CDV), a member of the family Paramyxoviridae and closely related to the measles virus (MeV) human pathogen. CDV establishes the infection by binding a receptor: signaling lymphocyte activation molecule family member 1 (SLAM/F1, or CD150), expressed by dendritic cells (DCs), subsets of thymocytes, macrophages, and T- and B-lymphocytes [7,8]. This facilitates the systemic dissemination whereby the virus interacts with a second receptor: nectin cell adhesion molecule 4 (nectin-4), expressed at the basolateral surface of epithelial cells [8], thereby infecting various tissues like fibroblasts, keratinocytes, gastrointestinal mucosa and respiratory tract. CDV can invade the central nervous system (CNS) and cause either acute polioencephalitis or demyelinating leukoencephalitis depending on the strain of CDV [10,11]
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