Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (Mpro) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the Mpro/BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor’s keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the Mpro active site adapt to the inhibitor, which appears to be an intrinsic property of Mpro. Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with Mpro which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.

The amount of ethylene oxide oligomerization for functionalization of poly(styryl)lithium in benzene at 25 °C has been determined using MALDI−TOF MS and 1H and 13C NMR. Chemically insignificant amounts of oligomer were found using 4 equiv of ethylene oxide ([EO]/[PLi]) after 12 h. For reactions times ranging from 12 h to 4 weeks using 10 equiv of ethylene oxide, the corresponding amounts of dimeric oligomerization varied from 4% to 34%. Trimeric oligomerization of ethylene oxide was detected after 1 week (1%) and 4 weeks (4%) by MALDI−TOF MS. The quantitative results from MALDI−TOF MS were in good agreement with results from both 1H and 13C NMR analyses. The quantitative aspects of MALDI−TOF MS compared to 1H and 13C NMR for the determination of the amount of EO oligomerization have been established through the synthesis and characterization of the model dimeric oligomer product, ω-(2-(2-hydroxyethoxy)ethyl)polystyrene.

Appreciable amounts of structural defects produced during Stille coupling polymerization have unexpected beneficial effects on the molecular ordering and charge transport performance of polymers.