2. Academic Validation
  3. Development of Potent, Selective Surrogate WNT Molecules and Their Application in Defining Frizzled Requirements

Development of Potent, Selective Surrogate WNT Molecules and Their Application in Defining Frizzled Requirements

  • Cell Chem Biol. 2020 May 21;27(5):598-609.e4. doi: 10.1016/j.chembiol.2020.02.009.
Hui Chen 1,  Chenggang Lu 1,  Brian Ouyang 1,  Haili Zhang 1,  Zhong Huang 1,  Diksha Bhatia 1,  Sung-Jin Lee 1,  Darshini Shah 1,  Asmiti Sura 1,  Wen-Chen Yeh 1,  Yang Li 2
Affiliations

Affiliations

  • 1 Surrozen Inc., 171 Oyster Point Boulevard, Suite 400, South San Francisco, CA 94080, USA.
  • 2 Surrozen Inc., 171 Oyster Point Boulevard, Suite 400, South San Francisco, CA 94080, USA. Electronic address: [email protected].
PMID: 32220333 DOI: 10.1016/j.chembiol.2020.02.009
Abstract

WNTs regulate myriad biological processes during embryonic development and are key regulators of stem cell function, tissue homeostasis, and injury repair in adults. The creation of WNT-based therapies has been hampered by challenges in developing soluble, potent, and selective Wnt molecules. Soluble Wnt surrogates have been reported, but they demonstrate relatively weak Wnt signaling activity. Here, we describe a platform for potent, selective Wnt surrogate generation. We identify multivalent binding to Frizzleds (FZDs) and low-density lipoprotein receptor-related proteins (LRPs) to be a requirement for maximal Wnt/β-catenin activation. Furthermore, we show that recruitment of two different FZDs together with LRP causes efficient signaling. Surrogate Wnt targeting either FZD1,2,7 or FZD5,8 induces expansive growth of intestinal organoids. This flexible Wnt surrogate platform yields potent agonists with any desired receptor specificity and will be useful for research and therapeutic applications for tissue regeneration.

Keywords

FZD; Frizzled; LRP; WNT; intestine; low-density lipoprotein receptor-related protein; organoid; stem cell; surrogate.

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