An update on the COVID Moonshot

On March 18, 2020, a group called the COVID Moonshot released crystal structures of 71 fragments bound to the SARS-CoV2 Mpro protein. The same day, they launched an online crowdsourcing initiative seeking ideas for how to advance these fragments, none of which had activity in an enzymatic assay. The results of this experiment in open science have just been published in Science, appropriately open-access.

 

Within the first week, the group received more than 2000 submissions. Ultimately more than 20,000 molecules were submitted, and all of these were evaluated in “alchemical free-energy calculations.” These are computationally intensive, requiring ~80 GPU hours per compound, so the consortium used the volunteer-based distributed computing network Folding@home. Compounds were evaluated not just for potency but also synthetic accessibility, and those that passed were synthesized at Enamine and tested in various functional assays.

 

In addition to accepting submissions for how to advance fragments, a core group of researchers proposed their own ideas. Interestingly, at least in the early stages of the project, this elite group did no better at coming up with more potent or synthetically accessible molecules, despite being intimately involved with the project. This finding validates the open-sourcing of ideas from the larger scientific community.

 

Ultimately more than 2400 compounds were synthesized, and more than 500 crystal structures were determined. All experimental results were posted online to help guide the synthesis of additional compounds. Speed was consistently prioritized, not just with high-throughput crystallography but also high-throughput chemistry and "direct-to-biology" screening of crude reaction mixtures.

 

The paper highlights one lead series, which originated from a community submission (TRY-UNI-714a760b-6, itself fragment-sized) inspired by merging overlapping fragments. This mid micromolar inhibitor was ultimately optimized to MAT-POS-e194df51-1, with mid-nanomolar activity in both biochemical and cell assays. (Despite a chloroacetamide in one of the original fragments and a nitrile in the final molecule, which is the warhead found in the approved covalent Mpro inhibitor nirmatrelvir, MAT-POS-e194df51-1 is non-covalent.) 

 

The molecule is potent against known SARS-CoV-2 variants, including recent ones such as Omicron. A crystal structure of the final molecule also overlays remarkably well onto the initial fragments.

 

The paper notes that there is still considerable work to do, particularly optimizing the pharmacokinetics to lower clearance and improve bioavailability. These efforts can take vast sums of time and money, and the lead series has been adopted by the Drugs for Neglected Diseases initiative for further development. Although a handful of drugs are already approved against SARS-CoV-2, there is room for improvement: Derek Lowe posted a vivid personal account of his experience on nirmatrelvir here.

 

When we wrote about the COVID Moonshot in March of 2020, we correctly predicted that vaccines would be approved before drugs from this effort emerged. Fortunately, our warning that “there will be a SARS-CoV-3” has not proven correct – yet. But open science endeavors such as the COVID Moonshot will help us prepare for this eventuality. We may not have made it to the moon yet, but perhaps we’ve learned how to leave Earth’s orbit.