Covid Moonshot yields novel coronavirus antivirals

A novel drug candidate for COVID-19 that targets SARS-CoV-2’s main protease (Mpro) 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 US National Institutes of Health (NIH), will continue developing antiviral drugs for severe acute respiratory syndrome (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, the researchers say.

The effort began with a dataset of combined crystallographic and electrophilic fragment screens of SARS-CoV-2’s 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 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. (The von Delfts are married.) She soon became the COVID Moonshot Consortium’s de facto project manager. Chemists from small and large biopharmaceutical companies, as well as academics, contributed possibilities.T

he COVID Moonshot team initially improved on these possibilities using cellular assays and a machine learning–based platform from the company PostEra. An “astonishing” number of pharmaceutical companies signed on to profile those compounds pro bono, says Annette von Delft. This generated multiple lead candidates.

The nonprofit Drugs for Neglected Diseases Initiative (DNDI) is helming the development of Moonshot’s most advanced lead, DNDI-6510, with funding from the Wellcome Trust. “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, Annette von Delft says.

If the DNDI experiment pans out, it may pave the way for other efforts to develop drugs to benefit global public health, even without a clear market.

Meanwhile, through an NIH grant, the consortium is also working on antivirals for more viruses. Ultimately, says Alpha Lee, chief scientific officer of PostEra, the dream is to develop a stockpile of inhibitors targeting proteins in every virus of pandemic concern. Researchers could then use this resource to swiftly develop effective antivirals if the need arose.

Even though the consortium’s drug candidates 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. When another pandemic hits, he says, “we are going to be relying on the molecules we are finding for this one.”