| Abstract: |
Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5′-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. |
| Notes: |
Article -- Export Date: 1 April 2022 -- Funding details: GC230724 -- Funding details: National Institutes of Health, NIH, LLS 1318-15, LLS 7014-17, P50 CA192937-03, P50 CA217694, R35 CA252982-01, RO1CA183876-05, RO1CA207217–03 -- Funding details: National Cancer Institute, NCI, P30 CA08748 -- Funding details: Texas Tech University, TTU -- Funding details: Deutsches Zentrum für Infektionsforschung, DZIF -- Funding details: Deutsche Forschungsgemeinschaft, DFG, A02, GRK2581, KFO309, SFB 1021, Z02, Z1 -- Funding details: Bundesministerium für Bildung und Forschung, BMBF -- Funding text 1: Funding: This research was funded by the LOEWE Center DRUID (projects A2 and B2, to A.G. and J.Z.), the German Center for Infection Research (DZIF), partner site Giessen-Marburg-Langen (TTU Emerging Infections, to J.Z. and S.P.), the Deutsche Forschungsgemeinschaft (SFB 1021 ‘RNA viruses: RNA metabolism, pathogenesis and host response’; projects A01 and A02, to J.Z. and R.K.H.; Z02, to T.H.; KFO309, project P3, to J.Z.; Z1 to J.P.M. and T.H.; GRK2581, project P10, to J.Z.), the German Federal Ministry for Education and Research (BMBF, COVINET, to J.Z.), the BMBF project HELIATAR (to A.G. and J.Z) and the von Behring-Roentgen Foundation (to J.Z.). Further support to H.G.W. was from the NCI Cancer Center Support Grant to MSKCC (CCSG, P30 CA08748), the Starr Cancer Consortium (GC230724) and from NIH grants RO1CA183876-05, RO1CA207217–03, R35 CA252982-01, P50 CA192937-03, P50 CA217694), LLS 7014-17, LLS 1318-15. -- Source: Scopus |
