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.
Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime. A deficiency of the iron transporter PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across the outer membrane. The deficiency of OmpK35/36 in Klebsiella pneumoniae and the overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.
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