Targeting STT3A and STT3B to Block Flavivirus Replication

AbstractMosquito borne flaviviruses cause disease worldwidewith members such as dengue virusDENVZika virusZIKVand west nile virusWNVinfecting more thanmillion individuals annuallyThe availability of small molecule antivirals that reduce flavivirus infection therefore could have an immediate and substantial impact on public health programs that seek to improve outcomes for populations infected with WNVDENVand ZIKVRecentlygenome wide screening using either insertional mutagenesis or CRISPR Casknockout approaches have identified subunits of the oligosaccharyltransferaseOSTspecifically STT A and STT Bas essential for the flavivirus life cycleDrug discovery efforts using a novel bioluminescent reporter that detects inhibition of OST function have also had recent success with the identification of novel small molecules that target the OSTThis class of inhibitors directly engage with the STT A and STT B subunits and therefore have the potential to be antiviral agents for the treatment of flavivirus infectionThe proposed research seeks to structurally optimize the potency and solubility of this drug like small molecule series in order to advance this therapeutic strategy for preclinical testing