bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–11–03
ten papers selected by
Henry Lamb, Queensland University of Technology
  1. Synthesis and Evaluation of 68Ga- and 177Lu-Labeled [Pro14]bombesin(8-14) Derivatives for Detection and Radioligand Therapy of Gastrin-Releasing Peptide Receptor-Expressing Cancer.
  2. Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases.
  3. Characterization of Macrocyclic Peptide Drug Interactions with Bile Salts and Biorelevant Colloids via Single Amino Acid Mutations and 1H Nuclear Magnetic Resonance (NMR) Spectroscopy.
  4. 310-Helix stabilization and screw sense control via stereochemically configured 4-atom hydrocarbon staples.
  5. Discovery of Highly Bioactive Peptides through Hierarchical Structural Information and Molecular Dynamics Simulations.
  6. Nanostructured lipid carriers decorated with polyphosphate coated linear and loop cell-penetrating peptides.
  7. Development of α-Helical Antimicrobial Peptides with Imperfect Amphipathicity for Superior Activity and Selectivity.
  8. Analytical and drug delivery strategies for short peptides: From manufacturing to market.
  9. Strategic design of GalNAc-helical peptide ligands for efficient liver targeting.
  10. Kalata B1 Enhances Temozolomide Toxicity to Glioblastoma Cells.
  1. Mol Pharm. 2024 Oct 26.
    Synthesis and Evaluation of 68Ga- and 177Lu-Labeled [Pro14]bombesin(8-14) Derivatives for Detection and Radioligand Therapy of Gastrin-Releasing Peptide Receptor-Expressing Cancer.
    Lei Wang, Hsiou-Ting Kuo, Devon E Chapple, Chao-Cheng Chen, Sara Kurkowska, Nadine Colpo, Carlos Uribe, François Bénard, Kuo-Shyan Lin.
      The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of cancers and represents a promising target for diagnosis and therapy. However, the extremely high accumulation in the pancreas observed for most of the clinically evaluated GRPR-targeted radiopharmaceuticals could limit their applications. In this study, we synthesized one GRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057) by replacing the 4-thiazolidinecarboxylic acid (Thz14) residue in our previously reported GRPR-targeted tracers with Pro14. The 68Ga and 177Lu labeling were conducted in HEPES (2 M, pH 5.0) buffer and acetate (0.1 M, pH 4.5) buffer, respectively, and the radiolabeled products were obtained in a 24-57% decay-corrected radiochemical yield and >92% radiochemical purity. The binding affinities (Ki) of Ga-ProBOMB5, Ga-LW02056, Ga-LW02057, and Lu-ProBOMB5 were measured via in vitro competition binding assays and were 12.2 ± 1.89, 14.7 ± 4.81, 13.8 ± 2.24, and 13.6 ± 0.25 nM, respectively. The PET imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice at 1 h post injection. [68Ga]Ga-ProBOMB5, [68Ga]Ga-LW02056, and [68Ga]Ga-LW02057 enabled clear tumor visualization in PET images. The tumor uptake values of [68Ga]Ga-ProBOMB5, [68Ga]Ga-LW02056, and [68Ga]Ga-LW02057 were 12.4 ± 1.35, 8.93 ± 1.96, and 7.64 ± 0.55%ID/g, respectively, and their average pancreas uptake values were minimal (0.60-1.37%ID/g). Longitudinal SPECT imaging and ex vivo biodistribution studies were also conducted for [177Lu]Lu-ProBOMB5 and clinically validated [177Lu]Lu-RM2. Despite comparable tumor uptake at 1 h post injection ([177Lu]Lu-ProBOMB5:8.09 ± 1.70%ID/g; [177Lu]Lu-RM2:7.73 ± 0.96%ID/g), a faster clearance from PC-3 tumor xenografts was observed for [177Lu]Lu-ProBOMB5, leading to a lower radiation-absorbed dose delivered to tumors. Our data demonstrate that [68Ga]Ga-ProBOMB5 is a promising tracer for clinical translation for detecting GRPR-expressing tumor lesions. However, further optimizations are needed for [177Lu]Lu-ProBOMB5 to prolong tumor retention for therapeutic applications.
    Keywords:  RM2; gallium-68; gastrin-releasing peptide receptor; lutetium-177; pancreas uptake
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c00952
  2. RSC Adv. 2024 Oct 29. 14(47): 34637-34642
    Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases.
    Daryl Ariawan, Kanishka P M Thananthirige, Ali El-Omar, Julia van der Hoven, Sian Genoud, Holly Stefen, Thomas Fath, Janet van Eersel, Lars M Ittner, Ole Tietz.
      Peptide therapeutics are an emerging class of drugs to treat neurodegenerative diseases by inhibiting protein-protein interactions (PPIs). Nerinetide has recently emerged as a promising therapeutic for the treatment of ischemic stroke and Alzheimer's Disease (AD). The design of this potent neuroprotective agent includes a cell penetrating peptide sequence that achieves delivery into neurons and a protein-protein inhibitory sequence that achieves inhibition of protein complex formation through mimicry. In this study, we deconstruct the nerinetide sequence and study the relationship between plasma stability, intraneuronal delivery and drug efficacy to provide design guidelines for the development of next generation, peptidic PPI inhibitors to treat neurodegenerative diseases.
    DOI:  https://doi.org/10.1039/d4ra05040a
  3. J Pharm Sci. 2024 Oct 23. pii: S0022-3549(24)00471-4. [Epub ahead of print]
    Characterization of Macrocyclic Peptide Drug Interactions with Bile Salts and Biorelevant Colloids via Single Amino Acid Mutations and 1H Nuclear Magnetic Resonance (NMR) Spectroscopy.
    Tahnee J Dening, José G Napolitano, Jessica L Ochoa, Justin T Douglas, Michael J Hageman.
      There is growing interest in the oral delivery of poorly permeable peptide drugs; however, the effect of biorelevant colloids found in the aqueous gastrointestinal environment on peptide drug solution behavior has been largely understudied. In this work, we detail the molecular level interactions between octreotide, a water-soluble macrocyclic peptide drug, and biorelevant colloids, i.e. bile salt micelles and bile salt-phospholipid mixed micelles, via dialysis membrane flux experiments and proton nuclear magnetic resonance (1H NMR) spectroscopy. A modified alanine scan was employed to generate eight mutated octreotide analogs; the impact of individual amino acid mutations on peptide dialysis membrane flux rates in micellar (trihydroxy and dihydroxy) bile salt solutions as well as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) was evaluated and compared against the parent peptide, octreotide. We show that octreotide interacts more strongly with dihydroxy bile salt micelles than trihydroxy bile salt micelles in solution, and in FaSSIF/FeSSIF media, octreotide mainly interacts with the phospholipid component. These interactions are largely mediated by hydrophobic interactions of octreotide's aromatic residues as well as electrostatic interactions between octreotide's basic Lys residue and terminal amine.
    Keywords:  Absorption; colloid(s); gastrointestinal; interaction(s); intestinal absorption; micelle(s); oral absorption; peptide delivery; peptide(s); phospholipid(s)
    DOI:  https://doi.org/10.1016/j.xphs.2024.10.021
  4. Bioorg Med Chem. 2024 Nov 15. pii: S0968-0896(24)00377-8. [Epub ahead of print]114 117963
    310-Helix stabilization and screw sense control via stereochemically configured 4-atom hydrocarbon staples.
    Duc V H Tran, Ha T N Nguyen, Hee-Chul Ahn, Young-Woo Kim.
      The 310-helix is a crucial secondary structure in proteins, playing an essential role in various protein-protein interactions, yet stabilizing it in biologically relevant peptides remains challenging. In this study, we investigated the potential of 4-atom hydrocarbon staples to stabilize 310-helices in peptides. Using ring-closing metathesis, we demonstrated that the staple's configuration is critical for both the stabilization and screw sense control of 310-helices. Circular dichroism spectroscopy revealed that the Ri,i+3S(4) staple-a 4-atom cross-link with (R)-configuration at the i position, (S)-configuration at the i + 3 position, and flanked by methyl groups-strongly induces right-handed 310-helices, especially in sequences with proteinogenic l-amino acids. Furthermore, multiple staples effectively stabilized longer peptides, underscoring the versatility of this approach for applications in peptide therapeutics and biomolecular engineering.
    Keywords:  3(10)-Helix; Hydrocarbon staples; Peptide conformation; Proteinogenic peptides; Screw sense control
    DOI:  https://doi.org/10.1016/j.bmc.2024.117963
  5. J Chem Inf Model. 2024 Oct 28.
    Discovery of Highly Bioactive Peptides through Hierarchical Structural Information and Molecular Dynamics Simulations.
    Shu Li, Lu Peng, Liuqing Chen, Linjie Que, Wenqingqing Kang, Xiaojun Hu, Jun Ma, Zengru Di, Yu Liu.
      Peptide drugs play an essential role in modern therapeutics, but the computational design of these molecules is hindered by several challenges. Traditional methods like molecular docking and molecular dynamics (MD) simulation, as well as recent deep learning approaches, often face limitations related to computational resource demands, complex binding affinity assessments, extensive data requirements, and poor model interpretability. Here, we introduce PepHiRe, an innovative methodology that utilizes the hierarchical structural information in peptide sequences and employs a novel strategy called Ladderpath, rooted in algorithmic information theory, to rapidly generate and enhance the efficiency and clarity of novel peptide design. We applied PepHiRe to develop BH3-like peptide inhibitors targeting myeloid cell leukemia-1, a protein associated with various cancers. By analyzing just eight known bioactive BH3 peptide sequences, PepHiRe effectively derived a hierarchy of subsequences used to create new BH3-like peptides. These peptides underwent screening through MD simulations, leading to the selection of five candidates for synthesis and subsequent in vitro testing. Experimental results demonstrated that these five peptides possess high inhibitory activity, with IC50 values ranging from 28.13 ± 7.93 to 167.42 ± 22.15 nM. Our study explores a white-box model driven technique and a structured screening pipeline for identifying and generating novel peptides with potential bioactivity.
    DOI:  https://doi.org/10.1021/acs.jcim.4c01006
  6. Int J Pharm. 2024 Oct 24. pii: S0378-5173(24)01078-0. [Epub ahead of print]667(Pt A): 124844
    Nanostructured lipid carriers decorated with polyphosphate coated linear and loop cell-penetrating peptides.
    Ahmad Saleh, Daniel Stengel, Martyna Truszkowska, Mariana Blanco Massani, Gergely Kali, Andreas Bernkop-Schnürch.
       AIM: This study aimed to evaluate the cellular uptake of nanostructured lipid carriers (NLCs) decorated with polyphosphate coated linear and loop cell-penetrating peptides (CPPs).
    METHODS: Linear-CPPs and loop-CPPs were synthesized via ring-opening polymerization and anchored on the surface NLCs, followed by coating with polyphosphate (PP). These nanocarriers (NCs) were characterized in terms of particle size, polydispersity index (PDI), and zeta potential. Cell viability and hemolysis, as well as enzyme-induced charge conversion via phosphate cleavage by free and membrane-bound intestinal alkaline phosphatase (IAP) were investigated. Cellular uptake studies by Caco-2 and HEK cells were quantitatively analyzed by flow cytometry and visualized by confocal microscopy.
    RESULTS: A shift in charge from positive to negative was obtained for both linear- and loop-CPPs-NLCs by coating with PP. PP-linear-CPPs-NLCs and PP-loop-CPPs-NLCs exhibited a particle size < 270 nm and a PDI of approximately 0.3. They had a minor effect on cell viability and caused in a concentration of 0.1 % (m/v) around 10 % hemolysis within 24 h. IAP triggered the cleavage and release of monophosphate from the surface of NLCs causing charge conversion from -22.2 mV to + 5.3 mV (Δ27.5 mV) for PP-linear-CPPs-NLCs and from -19.2 mV to + 11.9 mV (Δ31.1 mV) for PP-loop-CPPs-NLCs. Inhibition of alkaline phosphatase activity on Caco-2 and HEK cells confirmed the involvement of this enzyme in charge conversion. PP-linear-CPPs-NLCs showed on Caco-2 cells a higher uptake than PP-loop-CPPs-NLCs, whereas on HEK cells uptake of both types of NLCs was on the same level. The results of cellular uptake were confirmed visually by confocal microscopy.
    CONCLUSION: CPPs-NLCs coated with polyphosphate are a promising approach to overcome the polycationic dilemma and to enhance cellular uptake.
    Keywords:  Alkaline phosphatase; Cell-penetrating peptide; Cellular uptake; Charge conversion; Drug delivery systems; Nanostructured lipid carriers
    DOI:  https://doi.org/10.1016/j.ijpharm.2024.124844
  7. J Med Chem. 2024 Nov 01.
    Development of α-Helical Antimicrobial Peptides with Imperfect Amphipathicity for Superior Activity and Selectivity.
    Zhongxiang Wu, Ying Cai, Yajun Han, Yunhan Su, Tianyu Zhang, Xingyu Wang, An Yan, Liunan Wang, Sijing Wu, Gan Wang, Zhiye Zhang.
      The advancement of antimicrobial peptides (AMPs) as therapeutic agents is hindered by their poor selectivity. Recent evidence indicates that controlled disruption of the amphipathicity of α-helical AMPs may increase the selectivity. This study investigated the role of imperfect amphipathicity in optimizing AMPs with varied sequences to enhance their activity and selectivity. Among these, the lead peptide RI-18, characterized by an imperfectly amphipathic α-helical structure, demonstrated potent and broad-spectrum antibacterial activity without inducing hemolytic or cytotoxic effects. RI-18 effectively eliminated planktonic and biofilm-associated bacteria as well as persister cells and exhibited high bacterial plasma membrane affinity, inducing rapid membrane permeabilization and rupture. Notably, RI-18 significantly reduced bacterial loads without promoting bacterial resistance, highlighting its therapeutic potential. Overall, this study identified RI-18 as a promising antimicrobial candidate. The rational strategy of tuning imperfect amphipathicity to enhance the AMP activity and selectivity may facilitate the design and development of AMPs.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01855
  8. Anal Biochem. 2024 Oct 24. pii: S0003-2697(24)00243-4. [Epub ahead of print]696 115699
    Analytical and drug delivery strategies for short peptides: From manufacturing to market.
    Ashwini Chawathe, Vishal Ahire, Kshitiz Luthra, Bhumika Patil, Kalpna Garkhal, Nitish Sharma.
      In recent times, biopharmaceuticals have gained attention because of their tremendous potential to benefit millions of patients globally by treating widespread diseases such as cancer, diabetes and many rare diseases. Short peptides (SP), also termed as oligopeptides, are one such class of biopharmaceuticals, that are majorly involved in efficient functioning of biological systems. Peptide chains that are 2-20 amino acids long are considered as oligopeptides by researchers and are some of the functionally vital compounds with widespread applications including self-assembly material for drug delivery, targeting ligands for precise/specific targeting and other biological uses. Using functionalised biomacromolecules such as short chained peptides, helps in improving pharmacokinetic properties and biodistribution profile of the drug. Apart from this, functionalised SP are being employed as cell penetrating peptides and prodrug to specifically and selectively target tumor sites. In order to minimize any unwanted interaction and adverse effects, the stability and safety of SP should be ensured throughout its development from manufacturing to market. Formulation development and characterization strategies of these potential molecules are described in the following review along with various applications and details of marketed formulations.
    Keywords:  Anti-Cancer; Characterization; Drug delivery; Formulation; Oligopeptides; Peptides
    DOI:  https://doi.org/10.1016/j.ab.2024.115699
  9. Chem Sci. 2024 Oct 21.
    Strategic design of GalNAc-helical peptide ligands for efficient liver targeting.
    Takahito Ito, Nobumichi Ohoka, Michihiko Aoyama, Takashi Nishikaze, Takashi Misawa, Takao Inoue, Akiko Ishii-Watabe, Yosuke Demizu.
      There is a growing need for liver-selective drug delivery systems (DDS) in the treatment and diagnosis of liver diseases. The asialoglycoprotein receptor, a trimeric protein specifically expressed in the liver, is a key target for DDS. We hypothesized that peptides with reduced main-chain flexibility and strategically positioned N-acetylgalactosamine (GalNAc) moieties could enhance liver selectivity and uptake efficiency. The helical peptides designed in this study demonstrated superior uptake efficiency and liver selectivity compared with the conventional triantennary GalNAc DDS. These peptides also showed potential in protein delivery. Furthermore, we explored their application in lysosome-targeting chimeras (LYTACs), gaining valuable insights into the requirements for effective LYTAC functionality. This study not only highlights the potential of helical peptides as liver-selective DDS ligands, but also opens avenues for their use in various therapeutic and diagnostic applications, making significant strides in the targeted treatment of liver diseases.
    DOI:  https://doi.org/10.1039/d4sc05606j
  10. Biomedicines. 2024 Sep 28. pii: 2216. [Epub ahead of print]12(10):
    Kalata B1 Enhances Temozolomide Toxicity to Glioblastoma Cells.
    Samantha L Gerlach, James S Metcalf, Rachael A Dunlop, Sandra Anne Banack, Cheenou Her, Viswanathan V Krishnan, Ulf Göransson, Sunithi Gunasekera, Blazej Slazak, Paul Alan Cox.
      Glioblastoma (GBM) is the most aggressive cancer originating in the brain, but unfortunately combination treatments with resection, radiation, and chemotherapy are relatively ineffective. Therefore, novel methods of adjuvant therapy are critically needed. Cyclotides are plant-derived circular peptides that chemosensitize drug-resistant breast cancer to doxorubicin. We analyzed naturally occurring and synthetic cyclotides (Cycloviolacin O3, Cycloviolacin O19, natural Kalata B1, synthetic Kalata B1, and Vitri E) alone and in co-exposure treatments with the drug temozolomide (TMZ) in human glioblastoma cells. The cyclotides were identified by UPLC-PDA and HPLC-UV. The synthetic Kalata B1 sequence was verified with orbitrap LC-MS, and structural confirmation was provided by NMR spectroscopy. The cyclotides displayed dose-dependent cytotoxicity (IC50 values 2.4-21.1 µM) both alone and as chemosensitizers of U-87 MG and T 98 cells to TMZ. In fact, a 16-fold lower concentration of TMZ (100 µM) was needed for significant cytotoxicity in U-87 MG cells co-exposed to synthetic Kalata B (0.5 µM). Similarly, a 15-fold lower concentration of TMZ (75 µM) was required for a significant reduction in cell viability in T 98 cells co-exposed to synthetic Kalata B1 (0.25 µM). Kalata B1 remained stable in human serum stability assays. The data support the assertion that cyclotides may chemosensitize glioblastoma cells to TMZ.
    Keywords:  Viola; adjuvant therapy; chemosensitize; chemotherapy; cyclotides; glioblastoma; temozolomide
    DOI:  https://doi.org/10.3390/biomedicines12102216
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