DDX3, a new frontier in broad-spectrum antiviral therapy: synthesis of potential inhibitors

Viral infections inflict many serious human diseases with very high mortality rates. New drug-resistant strains are continually emerging due to the high viral mutation rate, which makes necessary to develop novel potent antivirals. Targeting cellular cofactor essential for the replication of different viruses but not for the cells represents a new strategy to combat infectious diseases and offers a higher genetic barrier to the development of the resistance. The DEAD-box RNA helicase DDX3 is a multifunctional protein involved in many aspects of RNA metabolism, including transcription, splicing, mRNA nuclear export, translation, RNA decay and ribosome biogenesis. DDX3 is a human host factor required for the replication of several DNA and RNA such as herpes virus, human immunodeficiency virus type 1, hepatitis C virus, Dengue virus and West Nile virus. Given the multifaceted functions of DDX3, this host factor represents a promising target to develop compounds with broad spectrum antiviral activity. In the last few years Prof. Botta’s research group has been identified several inhibitors of DDX3 proteins. From a medicinal chemistry point of view, DDX3 has multiple enzymatic activities, ATPase and RNA helicase, and functional domains that may be targeted by potential inhibitors. Prof. Botta’s research group, designed and validated the first small molecule DDX3 inhibitors specifically designed to target its RNA binding site (16d with anti-helicase activity against DDX3 IC50 = 0.3 μM). Pursuing this research line, a structure-based optimization process was prosecuted, resulting in the identification of a novel compound with the 1,2,4-oxadiazole nucleus UVR40, with anti-helicase activity against DDX3 IC50 = 0.13 μM. Thus, a small library of UVR40 derivatives has been designed by our computation group and synthesized during my PhD with the purpose to enlarge SAR knowledge, enhance its ADME properties and improve its activity profile. At the same time, with the attempt to enlarge our library of DDX3 inhibitors, Prof. Botta’s group built a novel library of “hybrid” compounds starting from the structures of two hit compounds previously discovered, 16d member of the urea series, and UVR06 characterized by a sulfonamide moiety. The novel library was synthesized, validated on the target enzyme, and evaluated against the West Nile virus (WNV) infection.