Structure-based design of prefusion-stabilized SARS-CoV-2 spikes

Ching‐Lin Hsieh(The University of Texas at Austin), Jory A. Goldsmith(The University of Texas at Austin), Jeffrey M. Schaub(The University of Texas at Austin), Andrea M. DiVenere(The University of Texas at Austin), Hung‐Che Kuo(The University of Texas at Austin), Kamyab Javanmardi(The University of Texas at Austin), Kevin Le(The University of Texas at Austin), Daniel Wrapp(The University of Texas at Austin), Alison G. Lee(The University of Texas at Austin), Yutong Liu(The University of Texas at Austin), Chia‐Wei Chou(The University of Texas at Austin), Patrick O. Byrne(The University of Texas at Austin), Christy K. Hjorth(The University of Texas at Austin), Nicole V. Johnson(The University of Texas at Austin), John Ludes-Meyers(The University of Texas at Austin), Annalee W. Nguyen(The University of Texas at Austin), Juyeon Park(The University of Texas at Austin), Nianshuang Wang(The University of Texas at Austin), Dzifa Amengor(The University of Texas at Austin), Jason J. Lavinder(The University of Texas at Austin), Gregory C. Ippolito(The University of Texas at Austin), Jennifer A. Maynard(The University of Texas at Austin), Ilya J. Finkelstein(The University of Texas at Austin), Jason S. McLellan(The University of Texas at Austin)
Science
July 23, 2020
10.1126/science.abd0826
Cited by 1,423Open Access
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Abstract

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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