Structure-based design of prefusion-stabilized SARS-CoV-2 spikes
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Open Access
- 18 September 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 369 (6510), 1501-1505
- https://doi.org/10.1126/science.abd0826
Abstract
The 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. Here, 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 ~10-fold higher expression than its parental construct and the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A 3.2 Å-resolution cryo-EM structure of HexaPro 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 SARS-CoV-2.Funding Information
- National Science Foundation (1453358)
- National Institutes of Health (R01-AI127521)
- National Institutes of Health (GM120554)
- National Institutes of Health (GM124141)
- National Institutes of Health (AI122753)
- Welch Foundation (F-1808)
- Welch Foundation (F-1767)
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