Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.

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An asymmetric synthesis of anti-aldol segments via a nonaldol route is described. The strategy involves a highly diastereoselective synthesis of functionalized tetrahydrofuran derivatives from optically active 4-phenylbutyrolactone. Treatment of the tetrahydrofuran derivatives with a Lewis acid and acetic anhydride provided the corresponding ring-opened styrene derivatives. Oxidative cleavage of the styrene derivatives provided access to the anti-aldol segments. The utility of this methodology was demonstrated by the synthesis of statine derivatives and pancreatic lipase inhibitor, (—)-tetrahydrolipstatin.

The asymmetric total synthesis of the anti-proliferative macrolide (+)-neopeltolide has been completed. The stereochemically defined trisubstituted tetrahydropyran ring was constructed via a catalytic hetero-Diels–Alder reaction creating two new chiral centers in a highly diastereoselective manner. The other key features of this synthesis included Brown’s asymmetric allylation to install the requisite C-11 and C-13 stereocenters. The synthesis of the oxazole side chain consisted of a hydrozirconation of an alkynyl stannane to establish the Z stereochemistry, followed by a palladium catalyzed cross coupling to introduce the desired Z olefin in the oxazole side chain.

Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).