COVID-19 has broken out since the end of December 2019 and is still spreading rapidly, which has been listed as an international concerning public health emergency. We found the Spike protein of SARS-CoV-2 contains a furin cleavage site, which did not exist in any other betacoronavirus subtype B. Based on a series of analysis, we speculate that the presence of a redundant furin cut site in its Spike protein is responsible for SARS-CoV-2’s stronger infectious than other coronaviruses, which leads to higher membrane fusion efficiency. Subsequently, a library of 4,000 compounds including approved drugs and natural products were screened against furin through structure-based virtual screening and then assayed for their inhibitory effects on furin activity. Among them, an anti-parasitic drug, Diminazene , showed the highest inhibition effects on furin with an IC 50 of 5.42 ± 0.11 μM, which might be used for the treatment of COVID-19.

Inspired by the success of dual targeting drugs, especially bispecific antibodies, we propose to combine the concept of protac and dual targeting to design and synthesize dual protac molecules with the function of degrading two completely different types of targets simultaneously. A library of novel dual targeting protac molecules have been rationally designed and prepared. A convergent synthetic strategy has been utilized to achieve high synthetic efficiency. These dual protac structures are characterized by using trifunctional natural amino acids as star-type core linkers to connect two independent inhibitors and E3 ligands together. In this study, gefitinib, olaparib, and CRBN or VHL E3 ligand were used as substrates to synthesize novel dual protacs. They successfully degraded both EGFR and PARP simultaneously in cancer cells. Being the first successful example of dual protacs, this technique will greatly widen the range of application of the protac method and open up a new field for drug discovery. File list (2) download file view on ChemRxiv dual_protac manuscript.pdf (1.02 MiB) download file view on ChemRxiv Supplementary Information.pdf (4.08 MiB)

A small library of C(1)-symmetric chiral diamines (L1-L9) was constructed via condensing exo-(-)-bornylamine or (+)-(1S,2S,5R)-menthylamine with various Cbz-protected amino acids. Among them, ligand L1/CuCl(2)·2H(2)O complex (2.5 mol %) shows outstanding catalytic efficiency for Henry reaction between a variety of aldehydes and nitroalkanes to afford the expected products in high yields (up to 98%) with excellent enantioselectivities (up to 99%) and moderate to good diastereoselectivities (up to 90:10). This process is air- and moisture tolerant and has been applied to the synthesis of (S)-2-amino-1-(3,4-dimethoxyphenyl)ethanol (9), a key intermediate for (S)-epinephrine and (S)-norepinephrine. On the basis of HRMS and X-ray diffraction analysis of the L1/CuCl(2) complex, a transition-state model was proposed to explain the origin of asymmetric induction. The low catalyst loading, excellent yields and enantioselectivities, inexpensive copper salt, and mild reaction conditions make our catalytic system to be practically useful.

Ruthenium-catalyzed regioselective oxidative cross-coupling/annulations of quinazolones with alkynes were successfully developed for direct access to fused polycyclic heteroarenes. The transformation proceeded well with a broad substrate scope under mild conditions to achieve moderate to high yields.

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