A protein therapeutic modality founded on molecular regulation

Chapman M. Wright, R. Clay Wright, James R. Eshleman, Marc Ostermeier

Research output: Contribution to journalArticlepeer-review

Abstract

The exquisite specificity of proteins is a key feature driving their application to anticancer therapies. The therapeutic potential of another fundamental property of proteins, their ability to be regulated by molecular cues in their environment, is unknown. Here, we describe a synthetic biology strategy for designing protein therapeutics that autonomously activate a therapeutic function in response to a specific cancer marker of choice. We demonstrate this approach by creating a prodrug-activating enzyme that selectively kills human cancer cells that accumulate the marker hypoxia-inducible factor 1α. This property arises primarily through increased cellular accumulation of the enzyme in the presence of the marker. Our strategy offers a platform for the development of inherently selective protein therapeutics for cancer and other diseases.

Original languageEnglish (US)
Pages (from-to)16206-16211
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number39
DOIs
StatePublished - Sep 27 2011

Keywords

  • Directed evolution
  • Enzyme/prodrug therapy
  • Protein engineering
  • Protein switch

ASJC Scopus subject areas

  • General

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