A Novel Sphingosine Kinase Inhibitor Suppresses Chikungunya Virus Infection

Abstract

Chikungunya virus (CHIKV) is a re-emerging arbovirus in the alphavirus genus. Upon infection, it can cause severe joint pain that can last years in some patients, significantly affecting their quality of life. Currently, there are no vaccines or anti-viral therapies available against CHIKV. Its spread to the Americas from the eastern continents has substantially increased the count of the infected by millions. Thus, there is an urgent need to identify therapeutic targets for CHIKV treatment. A potential point of intervention is the sphingosine-1-phosphate (S1P) pathway. Conversion of sphingosine to S1P is catalyzed by Sphingosine kinases (SKs), which we previously showed to be crucial pro-viral host factor during CHIKV infection. In this study, we screened inhibitors of SKs and identified a novel potent inhibitor of CHIKV infection—SLL3071511. We showed that the pre-treatment of cells with SLL3071511 in vitro effectively inhibited CHIKV infection with an EC50 value of 2.91 µM under both prophylactic and therapeutic modes, significantly decreasing the viral gene expression and release of viral particles. Our studies suggest that targeting SKs is a viable approach for controlling CHIKV replication.

Effective Suppression of Chikungunya Virus Infection in Cell Cultures using Hepatitis Delta Ribozymes

“…Recently, a promising vaccine candidate entered clinical trials (23), however, even with a viable vaccine there remain significant hurdles to effective prevention, containment, and control of any disease, especially in underdeveloped countries. There is a considerable amount of research devoted to the development of antivirals that may be useful as therapeutics for CHIKV disease (see 24 for review) including interferon (25), deubiquinating enzyme inhibitors (26), sphingosine kinase inhibitors (27), and radicol (28) and defective viral genomes (29).…”

Identification of tyrphostin AG879 and A9 inhibiting replication of Chikungunya virus by screening of a kinase inhibitor library

“…Kinase inhibitors, a largest and most functionally diverse gene family, are key regulators of cellular function and are associated with viral replication in influenza virus 16 , measles virus 17 , hepatitis C virus 18 , alphavirus 19 , dengue virus 20 , human immunodeficiency virus 21 , herpes simplex virus 22 and human papillomavirus 23 . Recent studies demonstrated that a sphingosine kinase inhibitor suppressed CHKV infection 19 , and Src family kinase inhibitors blocked the translation of alphavirus subgenomic mRNAs 24 . Some benzofurans were found to inhibit CHIKV-associated cell death in a dose-dependent manner by screening a kinase inhibitor library 25 .…”