Harvard College

Children's Medical Center Corporation

University of California

Liang Tao

Min Dong

Lisheng Peng

Rongsheng Jin

Sulyman Barkho

Peng Chen

Aina He

Provided herein are agents that bind to the lipid binding groove of Frizzled (FZD). In some embodiments, the agent is a fragment of TcdB corresponding to amino acids 1285-1804 of SEQ ID NO: 1. In some embodiments, binding of the agent to the lipid binding groove of FZD inhibits TcdB entry into cells, and/or inhibits Wnt signaling. Methods of treatinginfection (CDI) and methods of treating cancer are also provided.

Compositions and methods for inhibiting Wnt signaling

Disclosed herein is a botulinum neurotoxin (BoNT) polypeptide with a modified receptor binding domain (HC) having one or more amino acid mutations that modify the binding of the BoNT to the receptor. Specific mutations and combinations of mutations are also disclosed. Isolated modified HC, polypeptides comprising the modified HC, chimeric molecules, pharmaceutical compositions, and methods of making and using the same are also disclosed. Methods of identifying additional such modified receptor binding domains, are further disclosed.

Engineered botulinum neurotoxin

Disclosed herein are methods for the isolation and purification of a botulinum neurotoxin (BoNT) protein, or a polypeptide comprising a receptor binding domain of BoNT, from a solution. The method comprises contacting the solution containing the protein or polypeptide to a matrix which has attached thereto a non-toxic non-hemagglutinin (NTNHA) under conditions appropriate for binding, washing the matrix to thereby remove unbound materials, and eluting the protein or polypeptide with a solution that dissociates the bound protein from the NTNHA. Conditions appropriate for binding are a pH of less than 7.5 (e.g, 6). Conditions appropriate for dissociation are a pH greater than or equal to 7.5 (e.g., 8). Compositions specific to the methods are also disclosed.

Method for purification and activation of botulinum neurotoxin

Disclosed herein are botulinum neurotoxin (BoNT) polypeptides with a modified BoNT/B4 receptor binding domain (B4-H) having amino acid mutations that modify the binding of the BoNT to the human SytII receptor. Specific mutations and combinations of mutations are disclosed. Isolated modified Hs, polypeptides comprising such modified Hs, chimeric molecules, pharmaceutical compositions, and methods of making and using the same are also disclosed. Methods of identifying additional such modified receptor binding domains, are further disclosed.

The present disclosure relates to isolated polypeptides that inhibit Wnt signaling, pharmaceutical compositions comprising the isolated polypeptides, and methods of use thereof. Nucleic acids, cells, and methods of production related to the isolated polypeptides and compositions are also disclosed.

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Liang Tao