bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2023–12–10
six papers selected by
Henry Lamb, Queensland University of Technology
  1. Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.
  2. BrainPepPass: A Framework Based on Supervised Dimensionality Reduction for Predicting Blood-Brain Barrier-Penetrating Peptides.
  3. De Novo Single-Stranded RNA-Binding Peptides Discovered by Codon-Restricted mRNA Display.
  4. The discovery and evaluation of [18F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement.
  5. Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo.
  6. FRET-GP - A Local Measure of the Impact of Transmembrane Peptide on Lipids.
  1. Nat Commun. 2023 Dec 06. 14(1): 8064
    Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.
    Edin Muratspahić, Kristine Deibler, Jianming Han, Nataša Tomašević, Kirtikumar B Jadhav, Aina-Leonor Olivé-Marti, Nadine Hochrainer, Roland Hellinger, Johannes Koehbach, Jonathan F Fay, Mohammad Homaidur Rahman, Lamees Hegazy, Timothy W Craven, Balazs R Varga, Gaurav Bhardwaj, Kevin Appourchaux, Susruta Majumdar, Markus Muttenthaler, Parisa Hosseinzadeh, David J Craik, Mariana Spetea, Tao Che, David Baker, Christian W Gruber.
      Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA-KOR-Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.
    DOI:  https://doi.org/10.1038/s41467-023-43718-w
  2. J Chem Inf Model. 2023 Dec 06.
    BrainPepPass: A Framework Based on Supervised Dimensionality Reduction for Predicting Blood-Brain Barrier-Penetrating Peptides.
    Ewerton Cristhian Lima de Oliveira, Hannah Hirmz, Evelien Wynendaele, Juliana Auzier Seixas Feio, Igor Matheus Souza Moreira, Kauê Santana da Costa, Anderson H Lima, Bart De Spiegeleer, Claudomiro de Souza de Sales Júnior.
      Peptides that pass through the blood-brain barrier (BBB) not only are implicated in brain-related pathologies but also are promising therapeutic tools for treating brain diseases, e.g., as shuttles carrying active medicines across the BBB. Computational prediction of BBB-penetrating peptides (B3PPs) has emerged as an interesting approach because of its ability to screen large peptide libraries in a cost-effective manner. In this study, we present BrainPepPass, a machine learning (ML) framework that utilizes supervised manifold dimensionality reduction and extreme gradient boosting (XGB) algorithms to predict natural and chemically modified B3PPs. The results indicate that the proposed tool outperforms other classifiers, with average accuracies exceeding 94% and 98% in 10-fold cross-validation and leave-one-out cross-validation (LOOCV), respectively. In addition, accuracy values ranging from 45% to 97.05% were achieved in the independent tests. The BrainPepPass tool is available in a public repository for academic use (https://github.com/ewerton-cristhian/BrainPepPass).
    DOI:  https://doi.org/10.1021/acs.jcim.3c00951
  3. Biomacromolecules. 2023 Dec 05.
    De Novo Single-Stranded RNA-Binding Peptides Discovered by Codon-Restricted mRNA Display.
    Shota Nishikawa, Hidenori Watanabe, Naohiro Terasaka, Takayuki Katoh, Kosuke Fujishima.
      RNA-binding proteins participate in diverse cellular processes, including DNA repair, post-transcriptional modification, and cancer progression through their interactions with RNAs, making them attractive for biotechnological applications. While nature provides an array of naturally occurring RNA-binding proteins, developing de novo RNA-binding peptides remains challenging. In particular, tailoring peptides to target single-stranded RNA with low complexity is difficult due to the inherent structural flexibility of RNA molecules. Here, we developed a codon-restricted mRNA display and identified multiple de novo peptides from a peptide library that bind to poly(C) and poly(A) RNA with KDs ranging from micromolar to submicromolar concentrations. One of the newly identified peptides is capable of binding to the cytosine-rich sequences of the oncogenic Cdk6 3'UTR RNA and MYU lncRNA, with affinity comparable to that of the endogenous binding protein. Hence, we present a novel platform for discovering de novo single-stranded RNA-binding peptides that offer promising avenues for regulating RNA functions.
    DOI:  https://doi.org/10.1021/acs.biomac.3c01024
  4. Eur J Nucl Med Mol Imaging. 2023 Dec 05.
    The discovery and evaluation of [18F]BMS-986229, a novel macrocyclic peptide PET radioligand for the measurement of PD-L1 expression and in-vivo PD-L1 target engagement.
    David J Donnelly, Joonyoung Kim, Tritin Tran, Paul M Scola, Daniel Tenney, Adrienne Pena, Thomas Petrone, Yunhui Zhang, Kenneth M Boy, Michael A Poss, Erin L Cole, Matthew G Soars, Benjamin M Johnson, Daniel Cohen, Daniel Batalla, Patrick L Chow, Andrea Olga Shorts, Shuyan Du, Nicholas A Meanwell, Samuel J Bonacorsi.
       PURPOSE: A same-day PET imaging agent capable of measuring PD-L1 status in tumors is an important tool for optimizing PD-1 and PD-L1 treatments. Herein we describe the discovery and evaluation of a novel, fluorine-18 labeled macrocyclic peptide-based PET ligand for imaging PD-L1.
    METHODS: [18F]BMS-986229 was synthesized via copper mediated click-chemistry to yield a PD-L1 PET ligand with picomolar affinity and was tested as an in-vivo tool for assessing PD-L1 expression.
    RESULTS: Autoradiography showed an 8:1 binding ratio in L2987 (PD-L1 (+)) vs. HT-29 (PD-L1 (-)) tumor tissues, with >90% specific binding. Specific radioligand binding (>90%) was observed in human non-small-cell lung cancer (NSCLC) and cynomolgus monkey spleen tissues. Images of PD-L1 (+) tissues in primates were characterized by high signal-to-noise, with low background signal in non-expressing tissues. PET imaging enabled clear visualization of PD-L1 expression in a murine model in vivo, with 5-fold higher uptake in L2987 (PD-L1 (+)) than in control HT-29 (PD-L1 (-)) tumors. Moreover, this imaging agent was used to measure target engagement of PD-L1 inhibitors (peptide or mAb), in PD-L1 (+) tumors as high as 97%.
    CONCLUSION: A novel 18F-labeled macrocyclic peptide radioligand was developed for PET imaging of PD-L1 expressing tissues that demonstrated several advantages within a nonhuman primate model when compared directly to adnectin- or mAb-based ligands. Clinical studies are currently evaluating [18F]BMS-986229 to measure PD-L1 expression in tumors.
    Keywords:  PD-L1; PD-L1 expression; PD-L1 macrocyclic peptide PET ligand; [18F]BMS-986229
    DOI:  https://doi.org/10.1007/s00259-023-06527-3
  5. Nat Commun. 2023 Dec 05. 14(1): 8051
    Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo.
    Katarina Kulhankova, Soumba Traore, Xue Cheng, Hadrien Benk-Fortin, Stéphanie Hallée, Mario Harvey, Joannie Roberge, Frédéric Couture, Sajeev Kohli, Thomas J Gross, David K Meyerholz, Garrett R Rettig, Bernice Thommandru, Gavin Kurgan, Christine Wohlford-Lenane, Dennis J Hartigan-O'Connor, Bradley P Yates, Gregory A Newby, David R Liu, Alice F Tarantal, David Guay, Paul B McCray.
      Gene editing strategies for cystic fibrosis are challenged by the complex barrier properties of airway epithelia. We previously reported that the amphiphilic S10 shuttle peptide non-covalently combined with CRISPR-associated (Cas) ribonucleoprotein (RNP) enabled editing of human and mouse airway epithelial cells. Here, we derive the S315 peptide as an improvement over S10 in delivering base editor RNP. Following intratracheal aerosol delivery of Cy5-labeled peptide in rhesus macaques, we confirm delivery throughout the respiratory tract. Subsequently, we target CCR5 with co-administration of ABE8e-Cas9 RNP and S315. We achieve editing efficiencies of up-to 5.3% in rhesus airway epithelia. Moreover, we document persistence of edited epithelia for up to 12 months in mice. Finally, delivery of ABE8e-Cas9 targeting the CFTR R553X mutation restores anion channel function in cultured human airway epithelia. These results demonstrate the therapeutic potential of base editor delivery with S315 to functionally correct the CFTR R553X mutation in respiratory epithelia.
    DOI:  https://doi.org/10.1038/s41467-023-43904-w
  6. Langmuir. 2023 Dec 04.
    FRET-GP - A Local Measure of the Impact of Transmembrane Peptide on Lipids.
    Garima C N Thakur, Arunima Uday, Piotr Jurkiewicz.
      Reconstitution of a transmembrane protein in model lipid systems allows studying its structure and dynamics in isolation from the complexity of the natural environment. This approach also provides a well-defined environment for studying the interactions of proteins with lipids. In this work, we describe the FRET-GP method, which utilizes Förster resonance energy transfer (FRET) to specifically probe the nanoenvironment of a transmembrane domain. The tryptophan residues flanking this domain act as efficient FRET donors, while Laurdan acts as acceptor. The fluorescence of this solvatochromic probe is quantified using generalized polarization (GP) to report on lipid mobility in the vicinity of the transmembrane domain. We applied FRET-GP to study the transmembrane peptide WALP incorporated in liposomes. We found that the direct excitation of Laurdan to its second singlet state strongly contributes to GP values measured in FRET conditions. Removal of this parasitic contribution was essential for proper determination of GPFRET - the local analogue of classical GP parameter. The presence of WALP significantly increased both parameters but the local effects were considerably stronger (GPFRET ≫ GP). We conclude that WALP restricts lipid movement in its vicinity, inducing lateral inhomogeneity in membrane fluidity. WALP was also found to influence lipid phase transition. Our findings demonstrated that FRET-GP simultaneously provides local and global results, thereby enhancing the depth of information obtained from the measurement. We highlight the simplicity and sensitivity of the method, but also discuss its potential and limitations in studying protein-lipid interactions.
    DOI:  https://doi.org/10.1021/acs.langmuir.3c02505
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