The coronavirus disease
2019 (COVID-19) pandemic, caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted
in millions of deaths and threatens public health and safety. Despite
the rapid global spread of COVID-19 vaccines, effective oral antiviral
drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2
3CL protease inhibitor clinical candidate. S-217622 was
discovered via virtual screening followed by biological screening
of an in-house compound library, and optimization of the hit compound
using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current
outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic
profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication
of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor
could be a potential oral agent for treating COVID-19.
Transgenic rice containing an antisense cDNA for the ␣ subunit of rice heterotrimeric G protein produced little or no mRNA for the subunit and exhibited abnormal morphology, including dwarf traits and the setting of small seeds. In normal rice, the mRNA for the ␣ subunit was abundant in the internodes and f lorets, the tissues closely related to abnormality in the dwarf transformants. The position of the ␣-subunit gene was mapped on rice chromosome 5 by mapping with the restriction fragment length polymorphism. The position was closely linked to the locus of a rice dwarf mutant, Daikoku dwarf (d-1), which is known to exhibit abnormal phenotypes similar to those of the transformants that suppressed the endogenous mRNA for the ␣ subunit by antisense technology. Analysis of the cDNAs for the ␣ subunits of five alleles of Daikoku dwarf (d-1), ID-1, DK22, DKT-1, DKT-2, and CM1361-1, showed that these dwarf mutants had mutated in the coding region of the ␣-subunit gene. These results show that the G protein functions in the formation of normal internodes and seeds in rice.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.