Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses.

Tampere M, Pettke A, Salata C, Wallner O, Koolmeister T, Cazares-Körner A, Visnes T, Hesselman MC, Kunold E, Wiita E, Kalderén C, Lightowler M, Jemth AS, Lehtiö J, Rosenquist Å, Warpman-Berglund U, Helleday T, Mirazimi A, Jafari R, Puumalainen MR

Viruses 12 (12) 1423 [2020-12-10; online 2020-12-10]

Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies.

Global Proteomics and Proteogenomics [Service]

PubMed 33322045

DOI 10.3390/v12121423

Crossref 10.3390/v12121423

pii: v12121423
pmc: PMC7762994