Poster abstracts
Poster number 1 submitted by Jordan Hempfling
Rational design of cell-permeable cyclic peptides containing a D-Pro-L-Pro motif
Jin Wen (Department of Chemistry and Biochemistry and Ohio State Biochemistry Program, The Ohio State University), Hui Liao, Kye Stachowski (Department of Chemistry and Biochemistry and Ohio State Biochemistry Program, The Ohio State University), Jordan P. Hempfling (Department of Chemistry and Biochemistry and Ohio State Biochemistry Program, The Ohio State University), Ziping Qian (Department of Chemistry and Biochemistry and Ohio State Biochemistry Program, The Ohio State University), Chunhua Yuan (Campus Chemical Instrument Center, The Ohio State University), Mark P. Foster, Dehua Pei (Department of Chemistry and Biochemistry and Ohio State Biochemistry Program, The Ohio State University)
Abstract:
Macrocyclic peptides are capable of binding to challenging targets such as the flat protein surfaces on the interfaces of protein-protein interactions with high affinity and specificity, but they have poor membrane permeability. Herein, we discovered a constrained cyclic cell-penetrating peptide (CPP) containing a D-Pro-L-Pro motif, cyclo(AFΦrpPRRFQ) (where Φ is L-naphthylalanine, r is D-arginine, and p is D-proline). This strategy permitted the rational design of cell-permeable cyclic peptides of large ring sizes (up to 16 amino acids). We applied this novel strategy to design a potent cell-permeable, and biologically active cyclic peptidyl inhibitor, cyclo(YpVNFΦrpPRR) (where Yp is L-phosphotyrosine), against the Grb2 SH2 domain. Multidimensional NMR spectroscopic and circular dichroism analyses were carried out to reveal that the cyclic CPP and the Grb2 SH2 inhibitor assume a primarily random coil structure but have significant β-hairpin character surrounding the D-Pro-L-Pro motif. These results demonstrate that cyclo(AFΦrpPRRFQ) is an effective CPP for endocyclic (insertion of the cargo into the CPP ring) or exocyclic delivery of biological cargos (attachment of cargo to the Gln side chain).
Keywords: Cell-penetrating peptide, Cyclic peptide, Protein-protein interaction