Deep mutagenesis in the study of COVID-19: a technical overview for the proteomics community

Erik Procko

Research output: Contribution to journalArticlepeer-review


INTRODUCTION: The spike (S) of SARS coronavirus 2 (SARS-CoV-2) engages angiotensin-converting enzyme 2 (ACE2) on a host cell to trigger viral-cell membrane fusion and infection. The extracellular region of ACE2 can be administered as a soluble decoy to compete for binding sites on the receptor-binding domain (RBD) of S, but it has only moderate affinity and efficacy. The RBD, which is targeted by neutralizing antibodies, may also change and adapt through mutation as SARS-CoV-2 becomes endemic, posing challenges for therapeutic and vaccine development.

AREAS COVERED: Deep mutagenesis is a Big Data approach to characterizing sequence variants. A deep mutational scan of ACE2 expressed on human cells identified mutations that increase S affinity and guided the engineering of a potent and broad soluble receptor decoy. A deep mutational scan of the RBD displayed on the surface of yeast has revealed residues tolerant of mutational changes that may act as a source for drug resistance and antigenic drift.

EXPERT OPINION: Deep mutagenesis requires a selection of diverse sequence variants; an in vitro evolution experiment that is tracked with next-generation sequencing. The choice of expression system, diversity of the variant library and selection strategy have important consequences for data quality and interpretation.

Original languageEnglish (US)
Pages (from-to)633-638
Number of pages6
JournalExpert Review of Proteomics
Issue number9
StatePublished - 2020


  • COVID-19
  • Deep mutational scan
  • mutational landscape
  • decoy receptor
  • ACE2
  • severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • SARS coronavirus 2

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry


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