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A bicyclic peptide scaffold promotes phosphotyrosine mimicry and cellular uptake.


ABSTRACT: While peptides are promising as probes and therapeutics, targeting intracellular proteins will require greater understanding of highly structured, cell-internalized scaffolds. We recently reported BC1, an 11-residue bicyclic peptide that inhibits the Src homology 2 (SH2) domain of growth factor receptor-bound protein 2 (Grb2). In this work, we describe the unique structural and cell uptake properties of BC1 and similar cyclic and bicyclic scaffolds. These constrained scaffolds are taken up by mammalian cells despite their net neutral or negative charges, while unconstrained analogs are not. The mechanism of uptake is shown to be energy-dependent and endocytic, but distinct from that of Tat. The solution structure of BC1 was investigated by NMR and MD simulations, which revealed discrete water-binding sites on BC1 that reduce exposure of backbone amides to bulk water. This represents an original and potentially general strategy for promoting cell uptake.

SUBMITTER: Quartararo JS 

PROVIDER: S-EPMC4254597 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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A bicyclic peptide scaffold promotes phosphotyrosine mimicry and cellular uptake.

Quartararo Justin S JS   Eshelman Matthew R MR   Peraro Leila L   Yu Hongtao H   Baleja James D JD   Lin Yu-Shan YS   Kritzer Joshua A JA  

Bioorganic & medicinal chemistry 20141002 22


While peptides are promising as probes and therapeutics, targeting intracellular proteins will require greater understanding of highly structured, cell-internalized scaffolds. We recently reported BC1, an 11-residue bicyclic peptide that inhibits the Src homology 2 (SH2) domain of growth factor receptor-bound protein 2 (Grb2). In this work, we describe the unique structural and cell uptake properties of BC1 and similar cyclic and bicyclic scaffolds. These constrained scaffolds are taken up by ma  ...[more]

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