Rational design of cell-permeable cyclic peptides containing a d-Pro-l-Pro motif. Issue 20 (15th October 2020)

• Record Type: Journal Article
• Authors: Wen, Jin; Liao, Hui; Stachowski, Kye; Hempfling, Jordan P.; Qian, Ziqing; Yuan, Chunhua; Foster, Mark P.; Pei, Dehua
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 20(2020)
• Publication Date: 2020-10-15
• Subjects: Cell-penetrating peptide -- Cyclic peptide -- β-Hairpin -- Protein-protein interaction -- Grb2 SH2 domain; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115711
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Cyclic peptides are capable of binding to challenging targets (e.g., proteins involved in protein-protein interactions) with high affinity and specificity, but generally cannot gain access to intracellular targets because of poor membrane permeability. In this work, we discovered a conformationally 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). The structural constraints provided by cyclization and the d -Pro-l -Pro motif permitted the rational design of cell-permeable cyclic peptides of large ring sizes (up to 16 amino acids). This strategy was applied to design a potent, cell-permeable, and biologically active cyclic peptidyl inhibitor, cyclo(Y p VNFΦrpPRR) (where Y p is l -phosphotyrosine), against the Grb2 SH2 domain. Multidimensional NMR spectroscopic and circular dichroism analyses revealed that the cyclic CPP as well as the Grb2 SH2 inhibitor assume a predominantly random coil structure but have significant β-hairpin character surrounding the d -Pro-l -Pro motif. These results demonstrate cyclo(AFΦrpPRRFQ) as an effective CPP for endocyclic (insertion of cargo into the CPP ring) or exocyclic delivery of biological cargos (attachment of cargo to the Gln side chain).