bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–07–14
eight papers selected by
Henry Lamb, Queensland University of Technology
  1. Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.
  2. A novel bispecific peptide targeting PD-1 and PD-L1 with combined antitumor activity of T-cells derived from the patients with TSCC.
  3. Synthesis and Evaluation of the First 68Ga-Labeled C-Terminal Hydroxamate-Derived Gastrin-Releasing Peptide Receptor-Targeted Tracers for Cancer Imaging with Positron Emission Tomography.
  4. A peptide strategy for inhibiting different protein aggregation pathways.
  5. A live cell imaging-based assay for tracking particle uptake by clathrin-mediated endocytosis.
  6. Machine-Learning-Guided Peptide Drug Discovery: Development of GLP-1 Receptor Agonists with Improved Drug Properties.
  7. Structural Characterization of Peptide Antibodies.
  8. Recent Advances in Targeted Cancer Therapy: Are PDCs the Next Generation of ADCs?
  1. Bioorg Med Chem. 2024 Jul 06. pii: S0968-0896(24)00244-X. [Epub ahead of print]110 117830
    Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.
    Mirai Kage, Ryuji Hayashi, Atsushi Matsuo, Minoru Tamiya, Shino Kuramoto, Kazuhiro Ohara, Machiko Irie, Aya Chiyoda, Koji Takano, Toshiya Ito, Tomoya Kotake, Ryuuichi Takeyama, Shiho Ishikawa, Kenichi Nomura, Noriyuki Furuichi, Yuya Morita, Satoshi Hashimoto, Hatsuo Kawada, Yoshikazu Nishimura, Keiji Nii, Hitoshi Sase, Atsushi Ohta, Tetsuo Kojima, Hitoshi Iikura, Mikimasa Tanada, Takuya Shiraishi.
      Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.
    Keywords:  Cyclic peptide; KRAS inhibitor; LUNA18; Middle sized molecule; Orally bioavailable peptide; mRNA display library
    DOI:  https://doi.org/10.1016/j.bmc.2024.117830
  2. Int Immunopharmacol. 2024 Jul 08. pii: S1567-5769(24)01103-2. [Epub ahead of print]138 112582
    A novel bispecific peptide targeting PD-1 and PD-L1 with combined antitumor activity of T-cells derived from the patients with TSCC.
    Lili Wang, Junheng Zheng, Zhihao Tan, Yan Zhang, Hua Wang.
      Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are key immune checkpoints (ICs) that critically influence immunotherapy. Tumor resistance to single IC-targeting drugs has increased interest in dual-target drugs, which have shown feasibility for cancer treatment. In this study, we aimed to develop dual-target peptide drugs targeting the PD-1/PD-L1 pathway and to evaluate their efficacy compared to functional antibodies in enhancing the cytotoxicity of human T cells against tongue squamous carcinoma cell lines. Through sequence analysis and peptide truncation, we modified a pre-existing peptide named nABPD-1 targeting PD-1. Subsequently, we obtained two novel peptides named nABPD-2 and nABPD-3, with nABPD-2 showing an enhanced affinity for human PD-1 protein compared to nABPD-1. Importantly, nABPD-2 exhibited dual-targeting capability, possessing a high affinity for both PD-L1 and PD-1. Furthermore, nABPD-2 effectively promoted the cytotoxicity of human T cells against tongue squamous carcinoma cell lines, surpassing the efficacy of anti-PD-1 or anti-PD-L1 functional antibodies alone. Considering that nABPD-2 has lower production costs and dose requirements, it can potentially be used in therapeutic applications.
    Keywords:  Bispecific peptides; Cancer immunotherapy; PD-1, PD-L1; Tongue squamous cell carcinoma (TSCC)
    DOI:  https://doi.org/10.1016/j.intimp.2024.112582
  3. Molecules. 2024 Jun 28. pii: 3102. [Epub ahead of print]29(13):
    Synthesis and Evaluation of the First 68Ga-Labeled C-Terminal Hydroxamate-Derived Gastrin-Releasing Peptide Receptor-Targeted Tracers for Cancer Imaging with Positron Emission Tomography.
    Lei Wang, Hsiou-Ting Kuo, Chao-Cheng Chen, Devon Chapple, Nadine Colpo, Pauline Ng, Wing Sum Lau, Shireen Jozi, François Bénard, Kuo-Shyan Lin.
      Gastrin-releasing peptide receptor (GRPR), overexpressed in many solid tumors, is a promising imaging marker and therapeutic target. Most reported GRPR-targeted radioligands contain a C-terminal amide. Based on the reported potent antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH, we synthesized C-terminal hydroxamate-derived [68Ga]Ga-LW02075 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH) and [68Ga]Ga-LW02050 ([68Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH), and compared them with the closely related and clinically validated [68Ga]Ga-SB3 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt). Binding affinities (Ki) of Ga-SB3, Ga-LW02075, and Ga-LW02050 were 1.20 ± 0.31, 1.39 ± 0.54, and 8.53 ± 1.52 nM, respectively. Both Ga-LW02075 and Ga-LW02050 were confirmed to be GRPR antagonists by calcium release assay. Imaging studies showed that PC-3 prostate cancer tumor xenografts were clearly visualized at 1 h post injection by [68Ga]Ga-SB3 and [68Ga]Ga-LW02050 in PET images, but not by [68Ga]Ga-LW02075. Ex vivo biodistribution studies conducted at 1 h post injection showed that the tumor uptake of [68Ga]Ga-LW02050 was comparable to that of [68Ga]Ga-SB3 (5.38 ± 1.00 vs. 6.98 ± 1.36 %ID/g), followed by [68Ga]Ga-LW02075 (3.97 ± 1.71 %ID/g). [68Ga]Ga-SB3 had the highest pancreas uptake (37.3 ± 6.90 %ID/g) followed by [68Ga]Ga-LW02075 (17.8 ± 5.24 %ID/g), while the pancreas uptake of [68Ga]Ga-LW02050 was only 0.53 ± 0.11 %ID/g. Our data suggest that [68Ga]Ga-LW02050 is a promising PET tracer for detecting GRPR-expressing cancer lesions.
    Keywords:  SB3; gallium-68; gastrin-releasing peptide receptor; hydroxamate derivatives; pancreas uptake; positron emission tomography
    DOI:  https://doi.org/10.3390/molecules29133102
  4. Chemistry. 2024 Jul 07. e202400080
    A peptide strategy for inhibiting different protein aggregation pathways.
    Tommaso Garfagnini, Luca Ferrari, Margreet B Koopman, Francoise A Dekker, Sem Halters, Eline Van Kappel, Guy Mayer, Shachar Bressler, Madelon M Maurice, Stefan G D Rudiger, Assaf Friedler.
      Protein aggregation correlates with many human diseases. Protein aggregates differ in structure and shape. Strategies to develop effective aggregation inhibitors that reach the clinic failed so far. Here, we developed a family of peptides targeting early aggregation stages for both amorphous and fibrillar aggregates of proteins unrelated in sequence and structure. They act on dynamic precursors before mechanistic differentiation takes place. Using peptide arrays, we first identified peptides inhibiting the amorphous aggregation of a molten globular, aggregation-prone mutant of the Axin tumor suppressor. Optimization revealed that the peptides activity did not depend on their sequences but rather on their molecular determinants: a composition of 20-30% flexible, 30-40% aliphatic and 20-30% aromatic residues, a hydrophobicity/hydrophilicity ratio close to 1, and an even distribution of residues of different nature throughout the sequence. The peptides also suppressed fibrillation of Tau, a disordered protein that forms amyloids in Alzheimer's disease, and slowed down that of Huntingtin Exon1, an amyloidogenic protein in Huntington's disease, both entirely unrelated to Axin. Our compounds thus target early aggregation stages of different aggregation mechanisms, inhibiting both amorphous and amyloid aggregation. Such cross-mechanistic, multi-targeting aggregation inhibitors may be lead compounds for developing drug candidates against various protein aggregation diseases.
    Keywords:  amyloid fibrils; peptide arrays; peptide design; protein aggregation inhibition; tau
    DOI:  https://doi.org/10.1002/chem.202400080
  5. Methods Enzymol. 2024 ;pii: S0076-6879(24)00040-5. [Epub ahead of print]700 413-454
    A live cell imaging-based assay for tracking particle uptake by clathrin-mediated endocytosis.
    Grant Ashby, Kayla E Keng, Carl C Hayden, Jeanne C Stachowiak.
      A popular strategy for therapeutic delivery to cells and tissues is to encapsulate therapeutics inside particles that cells internalize via endocytosis. The efficacy of particle uptake by endocytosis is often studied in bulk using flow cytometry and Western blot analysis and confirmed using confocal microscopy. However, these techniques do not reveal the detailed dynamics of particle internalization and how the inherent heterogeneity of many types of particles may impact their endocytic uptake. Toward addressing these gaps, here we present a live-cell imaging-based method that utilizes total internal reflection fluorescence microscopy to track the uptake of a large ensemble of individual particles in parallel, as they interact with the cellular endocytic machinery. To analyze the resulting data, we employ an open-source tracking algorithm in combination with custom data filters. This analysis reveals the dynamic interactions between particles and endocytic structures, which determine the probability of particle uptake. In particular, our approach can be used to examine how variations in the physical properties of particles (size, targeting, rigidity), as well as heterogeneity within the particle population, impact endocytic uptake. These data impact the design of particles toward more selective and efficient delivery of therapeutics to cells.
    Keywords:  Clathrin-mediated endocytosis; Colocalization; Drug-carrier internalization; Drug-carrier properties; Endocytosis; Particle tracking; Small unilamellar vesicle
    DOI:  https://doi.org/10.1016/bs.mie.2024.02.010
  6. J Med Chem. 2024 Jul 08.
    Machine-Learning-Guided Peptide Drug Discovery: Development of GLP-1 Receptor Agonists with Improved Drug Properties.
    Jens Christian Nielsen, Claudia Hjo Rringgaard, Mads Mo Rup Nygaard, Anita Wester, Lisbeth Elster, Trine Porsgaard, Randi Bonke Mikkelsen, Silas Rasmussen, Andreas Nygaard Madsen, Morten Schlein, Niels Vrang, Kristoffer Rigbolt, Louise S Dalbo Ge.
      Peptide-based drug discovery has surged with the development of peptide hormone-derived analogs for the treatment of diabetes and obesity. Machine learning (ML)-enabled quantitative structure-activity relationship (QSAR) approaches have shown great promise in small molecule drug discovery but have been less successful in peptide drug discovery due to limited data availability. We have developed a peptide drug discovery platform called streaMLine, enabling rigorous design, synthesis, screening, and ML-driven analysis of large peptide libraries. Using streaMLine, this study systematically explored secretin as a peptide backbone to generate potent, selective, and long-acting GLP-1R agonists with improved physicochemical properties. We synthesized and screened a total of 2688 peptides and applied ML-guided QSAR to identify multiple options for designing stable and potent GLP-1R agonists. One candidate, GUB021794, was profiled in vivo (S.C., 10 nmol/kg QD) and showed potent body weight loss in diet-induced obese mice and a half-life compatible with once-weekly dosing.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c00417
  7. Methods Mol Biol. 2024 ;2821 195-204
    Structural Characterization of Peptide Antibodies.
    Anna Chailyan, Paolo Marcatili.
      The role of proteins as very effective immunogens for the generation of antibodies is indisputable. Nevertheless, cases in which protein usage for antibody production is not feasible or convenient compelled the creation of a powerful alternative consisting of synthetic peptides. Synthetic peptides can be modified to obtain desired properties or conformation, tagged for purification, isotopically labeled for protein quantitation or conjugated to immunogens for antibody production. The antibodies that bind to these peptides represent an invaluable tool for biological research and discovery. To better understand the underlying mechanisms of antibody-antigen interaction, here, we present a pipeline developed by us to structurally classify immunoglobulin antigen binding sites and to infer key sequence residues and other variables that have a prominent role in each structural class.
    Keywords:  Clustering; Linear epitope; Peptide antibody; Structure
    DOI:  https://doi.org/10.1007/978-1-0716-3914-6_15
  8. J Med Chem. 2024 Jul 09.
    Recent Advances in Targeted Cancer Therapy: Are PDCs the Next Generation of ADCs?
    Baochen Zhang, Mo Wang, Li Sun, Jiawei Liu, Libinghan Yin, Mingjing Xia, Ling Zhang, Xifu Liu, Yu Cheng.
      Antibody-drug conjugates (ADCs) comprise antibodies, cytotoxic payloads, and linkers, which can integrate the advantages of antibodies and small molecule drugs to achieve targeted cancer treatment. However, ADCs also have some shortcomings, such as non-negligible drug resistance, a low therapeutic index, and payload-related toxicity. Many studies have focused on changing the composition of ADCs, and some have even further extended the concept and types of targeted conjugated drugs by replacing the targeted antibodies in ADCs with peptides, revolutionarily introducing peptide-drug conjugates (PDCs). This Perspective summarizes the current research status of ADCs and PDCs and highlights the structural innovations of ADC components. In particular, PDCs are regarded as the next generation of potential targeted drugs after ADCs, and the current challenges of PDCs are analyzed. Our aim is to offer fresh insights for the efficient design and expedited development of innovative targeted conjugated drugs.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c00106
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