Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease

James Brett Case, Rita E. Chen, Longxing Cao, Baoling Ying, Emma S. Winkler, Max Johnson, Inna Goreshnik, Minh N. Pham, Swathi Shrihari, Natasha M. Kafai, Adam L. Bailey, Xuping Xie, Pei Yong Shi, Rashmi Ravichandran, Lauren Carter, Lance Stewart, David Baker, Michael S. Diamond

Research output: Contribution to journalArticlepeer-review


Despite the introduction of public health measures and spike protein-based vaccines to mitigate the COVID-19 pandemic, SARS-CoV-2 infections and deaths continue to have a global impact. Previously, we used a structural design approach to develop picomolar range miniproteins targeting the SARS-CoV-2 spike receptor-binding domain. Here, we investigated the capacity of modified versions of one lead miniprotein, LCB1, to protect against SARS-CoV-2-mediated lung disease in mice. Systemic administration of LCB1-Fc reduced viral burden, diminished immune cell infiltration and inflammation, and completely prevented lung disease and pathology. A single intranasal dose of LCB1v1.3 reduced SARS-CoV-2 infection in the lung when given as many as 5 days before or 2 days after virus inoculation. Importantly, LCB1v1.3 protected in vivo against a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions. These data support development of LCB1v1.3 for prevention or treatment of SARS-CoV-2 infection.

Original languageEnglish (US)
Pages (from-to)1151-1161.e5
JournalCell Host and Microbe
Issue number7
StatePublished - Jul 14 2021


  • COVID-19
  • SARS-CoV-2
  • intranasal
  • mice
  • miniprotein
  • pathogenesis
  • prophylaxis
  • receptor-binding domain
  • therapy
  • variants

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology


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