Identification of Broad-Spectrum Inhibitors against Flaviviral NS2B-NS3 Proteases

Authors

• V Purandare
• Y Yano
• CC Abnet
• H Poustchi
• G Roshandel
• F Kamangar
• P Boffetta
• P Brennan
• SM Dawsey
• E Vogtmann
• R Malekzadeh
• A Etemadi

Abstract

Flaviviruses, such as Dengue, West Nile, Yellow Fever, and Zika viruses, are mosquito-borne arboviruses with the potential to cause virus-induced diseases, including encephalitis and hemorrhagic fever, throughout the world. Despite the emergent spread of this public health threat, there are currently no drugs available for their treatment. Flaviviruses share epidemiological, structural, and ecologic features, and often different viruses can co-infect the same host. The identification of broad-spectrum inhibitors against flaviviruses is highly desirable, and therefore, targeting flaviviral NS2B-NS3 proteases, which are essential for viral replication, has become an attractive goal for antiviral drug development.

In this study, we designed and performed ultra-high-throughput screening (uHTS) to identify broad-spectrum inhibitory agents against four recombinant NS2B-NS3 viral proteases from multiple flaviviruses, including Dengue, West Nile, Yellow Fever, and Zika. To search for effective inhibitors, a total of 12,000 compounds from structurally diverse molecular libraries, as well as libraries of approved drugs and pharmacologically active compounds, were screened using fluorescence-based enzymatic assays in the automated 1536-well plate format. From the uHTS data, we identified 81 hits as broad-spectrum inhibitors, and an AI-driven QSAR model was employed to efficiently optimize these hits for lead development. The candidate inhibitors were further validated in viral infection assays.

Scientific Focus Area: Microbiology and Infectious Diseases

This page was last updated on Monday, September 25, 2023