X-ray crystallography performed at Argonne National Laboratory’s Advanced Photon Source (APS) was crucial to the development of Paxlovid, Pfizer’s antiviral drug that the Food and Drug Administration authorized for use on 22 December to treat COVID-19. The research was performed at an APS beamline and funded by a pharmaceutical industry consortium that includes Pfizer.
Data from clinical trials released on 14 December indicate that Paxlovid is 89% effective at preventing hospitalizations and deaths from COVID when taken within several days of the onset of symptoms, Pfizer said in a press release. The Biden administration has ordered 10 million courses of the antiviral drug, which is to be taken in combination with ritonavir, a common antiviral used for treating HIV.
Research performed at the APS and at Brookhaven National Laboratory’s National Synchrotron Light Source (NSLS) also was instrumental in the development of the Pfizer–BioNTech and Moderna mRNA vaccines (see Physics Today, April 2021, page 20). Those vaccines and others target the SARS-CoV-2 spike protein that latches onto human host cells. Paxlovid instead disables the main protease (Mpro), an enzyme necessary for viral replication. In vitro assays indicate the drug will perform against the Omicron variant, Pfizer says.
As successive variants of the virus, including Omicron, have evolved, the spike has mutated to evade detection by the immune system. Proteases, which are internal to the virus, are less prone to mutation because they do not change the virus’s outward appearance, says Lisa Keefe, executive director of the industry consortium known as the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT). Keefe is also vice president for advancing therapeutics at the Hauptman-Woodward Medical Research Institute, which operates the beamline exclusively for IMCA-CAT members.
Crystallography is a small part of drug development, but it is essential at two stages, Keefe says. It is first used to resolve the structure of a target protein and identify active sites to which a molecule might bind. The technique is then used in a trial-and-error process to screen compounds and find those that will bind to the protein with the required kinetics. Showing the drug candidate’s three-dimensional structure to the FDA is helpful, though not always necessary, when seeking approval, she says.
The Department of Energy, which owns the nation’s light sources, doesn’t charge for academic research provided the results are made public. By paying to use the APS, the five companies that are IMCA-CAT members—Pfizer, Merck, Bristol-Myers Squibb, AbbVie, and Novartis—can keep their data proprietary and their research secret.
Other synchrotrons such as the UK’s Diamond Light Source offer similar capabilities and paid access for proprietary research. But Diamond decided against having beamlines paid for and reserved for industry, says a spokesperson, so that they wouldn’t be closed off to other researchers. Proprietary access is restricted to 30% of the available time on any Diamond beamline.
The highly automated IMCA-CAT line conducts 20 000 experiments per year, often multiple times in a week for each member, Keefe says. “Everything funnels through doing a structure,” she says. “It can be a bottleneck, but we have very high throughput.”
APS director Stephen Streiffer says major pharmaceutical companies “have had a strong footprint at the APS for well over a decade.” Thirteen of the APS’s 65 beamlines are dedicated to structural biology. Eli Lilly and Co, which isn’t a member of IMCA-CAT, operates one; several others are used for university research sponsored by the National Institutes of Health.
Although the x-ray beam at NSLS-II in Brookhaven is 20–50 times as bright as the APS’s, the additional photons aren’t required for a “production beamline” such as the one used by IMCA-CAT. The more intense beams of NSLS-II are particularly useful for structural determinations using tiny or imperfect crystals, Streiffer says.
The APS, which opened in 1995, is due to be shut down next year for a yearlong upgrade that will boost its brightness by a factor of 500. Upgrades always involve a tradeoff between future and near-term science, says Streiffer. Keefe says that IMCA-CAT will continue its operations at other DOE light sources during the APS hiatus.
