Highlights d Remdesivir binding of active site of polymerase is conserved across all human CoVs d Remdesivir inhibits SARS-CoV-2 in primary and continuous human lung cell cultures d Remdesivir potency depends on cell-type-specific metabolism to its active form d Therapeutic remdesivir reduces viral loads and improves outcomes in mice

A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.

Super hybrid rice varieties with ideal plant architecture (IPA) have been critical in enhancing food security worldwide. However, the molecular mechanisms underlying their improved yield remain unclear. Here, we report the identification of a QTL, qWS8/ipa1-2D, in the super rice Yongyou12 (YY12) and related varieties. In-depth genetic molecular characterization of qWS8/ipa1-2D reveals that this newly identified QTL results from three distal naturally occurring tandem repeats upstream of IPA1, a key gene/locus previously shown to shape rice ideal plant architecture and greatly enhance grain yield. The qWS8/ipa1-2D locus is associated with reduced DNA methylation and a more open chromatin state at the IPA1 promoter, thus alleviating the epigenetic repression of IPA1 mediated by nearby heterochromatin. Our findings reveal that IPA traits can be fine-tuned by manipulating IPA1 expression and that an optimal IPA1 expression/dose may lead to an ideal yield, demonstrating a practical approach to efficiently design elite super rice varieties.

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