Two major flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), cause severe health and economic burdens worldwide. Recently, genome-wide screenings have uncovered the importance of regulators of the Hrd1 ubiquitin ligase-mediated endoplasmic reticulum (ER)-associated degradation (ERAD) pathway for flavivirus replication in host cells. Here we report the identification of the compound Bardoxolone methyl (CDDO-me) as a potent inhibitor of the Hrd1 ubiquitin ligase-mediated ERAD, which possesses a broad-spectrum activity against both DENV and ZIKV. Cellular thermal shift assay (CETSA) suggested that CDDO-me binds to grp94, a key component of the Hrd1 pathway, at a low nanomolar concentration, whereas interaction was not detected with its paralog Hsp90. CDDO-me and the grp94 inhibitor PU-WS13 substantially suppressed DENV2 replication and the cytopathic effects caused by DENV and ZIKV infection. The antiviral activities of both compounds were demonstrated for all four DENV serotypes and four ZIKV strains in multiple human cell lines. This study defines grp94 as a crucial host factor for flavivirus replication and identified CDDO-me as a potent small molecule inhibitor of flavivirus infection. Inhibition of grp94 may contribute to the antiviral activity of CDDO-me. Further investigation of grp94 inhibitors may lead to a new class of broad-spectrum anti-flaviviral medications.
Phytomining technology cultivates hyperaccumulator plants on heavy metal contaminated soils, followed by biomass harvesting and incineration to recover valuable metals, offering an opportunity for resource recycling and soil remediation. Large areas of ultramafic soils, naturally rich in nickel (Ni), are present in numerous places around the world. As an environmentally friendly and cost-effective soil remediation technology, phytomining has a broad application prospect in such areas and thus has attracted great attention from global researchers. The key processes of phytomining include: (1) high-selectivity response of hyperaccumulator plants to Ni the underlying mechanisms involved in the rhizosphere; (2) underlying mechanisms of high-efficiency uptake and translocation of Ni in hyperaccumulators; and (3) resource recycling of high-added value Ni products from the Ni-rich bio-ore of hyperaccumulators. In recent 30 years, phytomining practices have successfully carried out in United States, Albania and Malaysia. However, the research and application of this technology in China are still in the fledging stage. This paper reviews the key processes and research progress of phytomining, and points out the bottleneck, to provide theoretical basis and technical guidance for phytomining.