The proteins were templated on the designed ankyrin repeat protein (DARPin), a synthetic scaffold inspired by a class of binding proteins commonly found in nature. Compared to conventional antibody-based drugs, DARPins are less prone to “go bad” during prolonged storage at moderate-to-high temperatures and can be made in large quantities at low cost, making DARPins potentially much more affordable. In addition, since DARPins are about one-eighth the size of an antibody, they have the capacity to access specific therapeutically important “hot spots” on a disease-related protein with greater precision.
In this study, the researchers created two DARPin molecules that assemble in groups of three and block the interaction between the primary protein used by the COVID-19 virus to enter cells and its partner on host cells, thus stopping the virus in its tracks. When delivered into the nose of animal models with the COVID-causing virus, the DARPins reduced the amount of virus that accumulate in the airways by up to 100-fold and significantly reduced disease progression. What’s more, the DARPins were effective not only against the original variant, but also all of the newer COVID-causing variants, including the omicron strain. The researchers attribute the broad effectiveness of the DARPins to their engineering design, which resulted in DARPins able to mimic a key interface on the cellular receptor needed by the virus to enter cells.
“This study offers the possibility of an on-demand nasal spray able to tackle COVID either before or after virus exposure,” Chen said. The team’s discovery provides another, potentially lower-cost therapeutic option for those who cannot receive traditional vaccines or are considered high risk.
The DARPin molecules were engineered by Vikas Chonira, PhD, with assistance from Rudo Simeon, PhD, both postdoctoral fellows in the Chen lab. This research is part of a larger collaborative effort that included Michael S. Diamond, MD, PhD, from Washington University; Peter D. Kwong, PhD, from the National Institutes of Health; and Zhiqiang An, PhD, from University of Texas Health Houston. Funding for the Chen lab is provided by the NIH New Innovator Award.
Karuppiah Chockalingam, PhD, Research Assistant Professor at the School of Medicine contributed to this article.