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He, Yan; Murby, Susan; Gifford, Larry; Collett, Andrew; Warhurst, Geoffrey; Douglas, Kenneth T.; Rowland, Malcolm; Ayrton, John

doi:10.1023/a:1016440707092

Cited by 29 publications

(5 citation statements)

References 17 publications

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“…Previous studies have indicated that d-peptides or d-proteins composed of d-amino acids are potential therapeutic agents with long half-lives in vivo and even oral bioavailability. [10] To find d-peptides that can bind to at arget protein of interest, the method of choice is mirror-image phage display. [10a, 11] In this technology,t he mirror image (a d-protein) of the natural ltarget protein is made by chemical synthesis.This d-protein is used to screen for binding of l-peptides displayed on phages.…”

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confidence: 99%

Blocking of the PD‐1/PD‐L1 Interaction by a D‐Peptide Antagonist for Cancer Immunotherapy

et al. 2015

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Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound (D) PPA-1 could bind PD-L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that (D) PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.

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mentioning

confidence: 99%

Blocking of the PD‐1/PD‐L1 Interaction by a D‐Peptide Antagonist for Cancer Immunotherapy

et al. 2015

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“…[10] To find d-peptides that can bind to at arget protein of interest, the method of choice is mirror-image phage display. Previous studies have indicated that d-peptides or d-proteins composed of d-amino acids are potential therapeutic agents with long half-lives in vivo and even oral bioavailability.…”

mentioning

confidence: 99%

Blocking of the PD‐1/PD‐L1 Interaction by a D‐Peptide Antagonist for Cancer Immunotherapy

Chang

Liu

et al. 2015

Angewandte Chemie

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Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as ap romising immunotherapyf or treating cancers.U sing the technology of mirror-image phage display,wedeveloped the first hydrolysisresistant d-peptide antagonists to target the PD-1/PD-L1 pathway.T he optimizedc ompound D PPA-1 could bind PD-L1 at an affinity of 0.51 mm in vitro.Ablockade assaya tt he cellular level and tumor-bearing mice experiments indicated that D PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo.T hus d-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.Scheme 1. A) The PD-1/PD-L1 interaction mediates cancer immune escape. B) d-Peptide antagonists targeting PD-L1 can inhibit the PD-1/ PD-L1 interaction for cancer immunotherapy.

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“…Certain physicochemical properties are typically predictive of the intrinsic cell membrane permeation of a molecule via the transcellular pathway. For instance, as the molecular surface area or polar surface area of a transcellular permeant increases, its cell membrane permeation will decrease. ,− In contrast, the relationship between cLogP and cell membrane permeation is nonlinear, i.e., the permeability decreases and plateaus at both low (e.g., negative) and high cLogP values…”

Section: Resultsmentioning

confidence: 99%

Effects of Amino Acid Chirality and the Chemical Linker on the Cell Permeation Characteristics of Cyclic Prodrugs of Opioid Peptides

et al. 2006

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Previously, our laboratory showed that the oxymethyl-modified coumarinic acid (OMCA) cyclic prodrug of the opioid peptide DADLE ([D-Ala2,D-Leu5]-Enk, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) exhibited low permeation across both the intestinal mucosa and the blood-brain barrier (BBB). This low cell permeation arose from its strong substrate activity for efflux transporters in these biological barriers. In an attempt to determine whether the chirality of the amino acid asymmetric centers could influence the solution structure of the cyclic prodrugs and thus their substrate activities for efflux transporters, we synthesized cyclic prodrugs of the opioid peptides H-Tyr-Ala-Gly-Phe-D-Leu-OH ([Ala2,D-Leu5]-Enk), H-Tyr-D-Ala-Gly-Phe-Leu-OH ([D-Ala2,Leu5]-Enk), and H-Tyr-Ala-Gly-Phe-Leu-OH ([Ala2,Leu5]-Enk). In an attempt to determine whether the chemical linker (OMCA) bestowed efflux substrate activity on the cyclic prodrugs, we synthesized capped linear derivatives (acetylated on the N-terminal and amidated on the C-terminal end) of [Ala2,D-Leu5]-Enk, [D-Ala2,Leu5]-Enk, and [Ala2,Leu5]-Enk. The solution conformations of the cyclic prodrugs were determined by molecular dynamics simulations using two-dimensional NMR data. The physicochemical properties (molecular surface area, polar surface area, and cLogP) were estimated computationally using Sybyl. Cell permeation characteristics were assessed using Caco-2 cells in the presence and absence of known inhibitors of efflux transporters. Despite apparent differences in their solution conformations and their physicochemical properties, the cyclic prodrugs of DADLE, [Ala2,D-Leu5]-Enk, [D-Ala2,Leu5]-Enk, and [Ala2,Leu5]-Enk all exhibited strong substrate activity for efflux transporters in Caco-2 cells. In contrast, the capped linear derivatives of [Ala2,D-Leu5]-Enk, [D-Ala2,Leu5]-Enk, and [Ala2,Leu5]-Enk exhibited very poor substrate activity for efflux transporters in Caco-2 cells. Therefore, the substrate activities of the cyclic prodrugs for efflux transporters in Caco-2 cells and in the intestinal mucosa and the BBB in vivo are most likely due to the chemical linker used to prepare these molecules and/or its effect on solution structures of the prodrugs.

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Abstract: This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.

Cited by 29 publications

References 17 publications

Blocking of the PD‐1/PD‐L1 Interaction by a D‐Peptide Antagonist for Cancer Immunotherapy

Blocking of the PD‐1/PD‐L1 Interaction by a D‐Peptide Antagonist for Cancer Immunotherapy

Blocking of the PD‐1/PD‐L1 Interaction by a D‐Peptide Antagonist for Cancer Immunotherapy

Effects of Amino Acid Chirality and the Chemical Linker on the Cell Permeation Characteristics of Cyclic Prodrugs of Opioid Peptides

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