Covid Moonshot yields novel coronavirus antivirals

A novel drug for Covid-19 that targets SARS-CoV-2’s main protease (Mpro) in preclinical development is one of several potential antiviral drugs to be identified through an open-source science project called the Covid Moonshot Consortium (Science 2023, DOI: 10.1126/science.abo7201). The consortium, which began as a grassroots volunteer effort but is now funded by the National Institutes of Health, will continue developing antiviral drugs for SARS and other viruses of pandemic concern.

The success of the consortium, to which 212 scientists from 47 organizations across 25 countries contributed, demonstrates the power of open-source drug discovery for urgent public health problems such as pandemic preparedness, the researchers say.

“I’m not saying that crowdsourcing is the way to go for all projects, but in select cases it can really increase engagement with the global [science] community, says Alpha Lee, chief scientific officer of PostEra, a machine learning medicinal chemistry company.

The effort began with a dataset of combined crystallographic and electrophilic fragment screens of SARS-CoV-2’s main protease (Mpro), generated by structural biologists Frank von Delft and Martin Walsh at Diamond Light Source, the UK’s national synchrotron science facility, and chemical biologist Nir London at the Weizmann Institute of Science. In March 2020, the researchers loaded the data onto a website and tweeted an open invitation to scientists worldwide to design potential compounds based on the fragment hits, promising to make and test those that looked feasible.

“It kind of snowballed from there,” says Annette von Delft, a translational scientist at the University of Oxford. (She and Frank von Delft are married.) She soon became the Covid Moonshot Consortium’s de facto project manager. Chemists from biopharma companies large and small, as well as academics, contributed possibilities.

Initially, the core Covid Moonshot team improved on these possibilities using cellular assays and PostEra’s machine learning–based lead optimization platform. Then, after they synthesized the most promising compounds, an “astonishing” number of pharmaceutical companies signed on to profile those compounds pro bono, says Annette von Delft, generating multiple lead candidates.

Since 2020, several drugs targeting Mpro have emerged. But the consortium’s structure-based approach will potentially yield drugs that work differently and thus have a different resistance profile and fewer side effects. The nonprofit Drugs for Neglected Diseases Initiative (DNDI) is heading up the development of Moonshot’s most advanced lead, DNDI-6510, funded by the Wellcome Trust. “To our knowledge, this is the only compound without a patent that is being developed in this way,” Annette von Delft says. “It’s basically a real-life experiment” to see if a development pathway with no obvious return on investment can produce a drug that is globally and equitably distributed.

It’s tough to replicate the motivations that brought all the players together for the Covid Moonshot initiative, says Annette von Delft. “But I do think there’s a lot of goodwill when it comes to neglected diseases,” she notes. If the DNDI experiment pans out, it may pave the way for other efforts to tap contributions from pharma in designing drugs to benefit global public health, even without a clear market.

Meanwhile, through a grant from the National Institutes of Health, the consortium is also working on antivirals for flaviviruses and picornaviruses. Ultimately, says Lee, the dream for pandemic preparedness would be to develop a stockpile of open-source inhibitors targeting proteins in every virus of pandemic concern. Researchers could then build off molecules in this “global toolbox” to develop antivirals in case of a pandemic.

Even though the consortium’s drugs aren’t yet ready, the effort is enormously useful, says Brian Shoichet, a pharmaceutical scientist at the University of California, San Francisco, who was not involved in the research but coauthored a commentary article accompanying the Covid Moonshot paper. “There’s going to be another pandemic—it’s just a question of when,” says Shoichet. “And when it hits we are going to be relying on the molecules we are finding for this one—so let’s find some more please.”