ABSTRACT
Stability assessment of drugs in space is particularly important for future missions., In space there are multiple factors, such as the variability of the conditions (radiation, microgravity, vacuum etc.) that could affect the reliability and reproducibility of the data. Therefore, we investigated the stability of an anti-Covid drug formulation, Remdesivir (RDV) sulfobutylether-beta-cyclodextrin (SBECD) complex, in two separate flight experiments on the International Space Station (ISS). While HPLC/MS studies revealed no degradation of the cyclodextrin excipient in any of the samples investigated in both missions, RDV purity analysis of the RDV/SBECD complex after the first mission revealed different stabilities and altered degradation in space and on Earth. This latter interesting finding was not supported by the second mission, where no differences in the drug stabilities were identified. This anomaly highlighted the importance of standardization together with increased control of the variable parameters during the entire space missions and the terrestrial control experiments.
ABSTRACT
COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments was progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.