Journal
SCIENCE
Volume 369, Issue 6510, Pages 1501-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abd0826
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Funding
- NIH [R01-AI127521, GM120554, GM124141, AI122753, 75N93019C00050]
- Bill & Melinda Gates Foundation
- Welch Foundation [F-1808, F-1767]
- NSF [1453358]
- National Cancer Institute's National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research [HSSN261200800001E]
- University of Texas College of Natural Sciences
- CPRIT [RR160023]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1453358] Funding Source: National Science Foundation
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The coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S) protein, which is metastable and difficult to produce recombinantly. We characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting higher expression than its parental construct (by a factor of 10) as well as the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A cryo-electron microscopy structure of HexaPro at a resolution of 3.2 angstroms confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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