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

Ching Lin Hsieh, Jory A. Goldsmith, Jeffrey M. Schaub, Andrea M. DiVenere, Hung Che Kuo, Kamyab Javanmardi, Kevin C. Le, Daniel Wrapp, Alison G. Lee, Yutong Liu, Chia Wei Chou, Patrick O. Byrne, Christy K. Hjorth, Nicole V. Johnson, John Ludes-Meyers, Annalee W. Nguyen, Juyeon Park, Nianshuang Wang, Dzifa Amengor, Jason J. LavinderGregory C. Ippolito, Jennifer A. Maynard, Ilya J. Finkelstein, Jason S. McLellan

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)1501-1505
Number of pages5
JournalScience
Volume369
Issue number6510
DOIs
StatePublished - Sep 18 2020

Keywords

  • Amino Acid Substitution
  • Betacoronavirus/chemistry
  • COVID-19 Vaccines
  • Coronavirus Infections/prevention & control
  • Cryoelectron Microscopy
  • Humans
  • Proline/chemistry
  • Protein Domains
  • Protein Stability
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus/chemistry
  • Viral Vaccines/chemistry

ASJC Scopus subject areas

  • General

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