bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–02–18
twelve papers selected by
Henry Lamb, Queensland University of Technology
  1. Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic.
  2. Lipid bilayer membrane permeability mechanism of the K-Ras(G12D)-inhibitory bicyclic peptide KS-58 elucidated by molecular dynamics simulations.
  3. Biocompatible strategies for peptide macrocyclisation.
  4. Discovery and characterization of anti-cancer peptides from a random peptide library.
  5. Peptide-based inhibitors targeting the PD-1/PD-L1 axis: potential immunotherapeutics for cancer.
  6. Structure-Guided Discovery of PD-1/PD-L1 Interaction Inhibitors: Peptide Design, Screening, and Optimization via Computation-Aided Phage Display Engineering.
  7. Cell-Penetrating Peptides as Keys to Endosomal Escape and Intracellular Trafficking in Nanomedicine Delivery.
  8. An Endosomal Escape Trojan Horse Platform to Improve Cytosolic Delivery of Nucleic Acids.
  9. Peptide Translocation Across Asymmetric Phospholipid Membranes.
  10. Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design.
  11. Stabilizing Scaffold for Short Peptides Based on Knottins.
  12. Induction of stearoyl-CoA desaturase confers cell density-dependent ferroptosis resistance in melanoma.
  1. ACS Pharmacol Transl Sci. 2024 Feb 09. 7(2): 309-334
    Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic.
    Syed Faheem Askari Rizvi, Linjie Zhang, Haixia Zhang, Quan Fang.
      The emergence of peptide-drug conjugates (PDCs) that utilize target-oriented peptide moieties as carriers of cytotoxic payloads, interconnected with various cleavable/noncleavable linkers, resulted in the key-foundation of the new era of targeted therapeutics. They are capable of retaining the integrity of conjugates in the blood circulatory system as well as releasing the drugs at the tumor microenvironment. Other valuable advantages are specificity and selectivity toward targeted-receptors, higher penetration ability, and drug-loading capacity, making them a suitable candidate to play their vital role as promising carrier agents. In this review, we summarized the types of cell-targeting (CTPs) and cell-penetrating peptides (CPPs) that have broad applications in the advancement of targeted drug-delivery systems (DDS). Moreover, the techniques to overcome the limitations of peptide-chemistry for their extensive implementation to construct the PDCs. Besides this, the diversified breakthrough of linker chemistry, and ample knowledge of various cytotoxic payloads used in PDCs in recent years, as well as the mechanism of action of PDCs was critically discussed. The principal aim is to provide scattered and diversified knowledge in one place and to help researchers understand the pinching knots in the science of PDC development, also their progression toward a bright future for PDCs as novel theranostics in clinical practice.
    DOI:  https://doi.org/10.1021/acsptsci.3c00269
  2. Bioorg Med Chem Lett. 2024 Feb 09. pii: S0960-894X(24)00051-9. [Epub ahead of print]100 129649
    Lipid bilayer membrane permeability mechanism of the K-Ras(G12D)-inhibitory bicyclic peptide KS-58 elucidated by molecular dynamics simulations.
    Kotaro Sakamoto, Takatsugu Hirokawa.
      Peptides are mid-size molecules (700-2000 g/mol) and have attracted particular interest as therapeutic modalities as they are superior in controlling protein-protein interactions, a process that is a typical drug target category, compared with small molecules (<500 g/mol). In 2020, we identified KS-58 (1333 g/mol) as a K-Ras(G12D)-inhibitory bicyclic peptide and suggested its cell membrane permeability. However, the membrane permeability mechanism had not been elucidated. In this study, we aim to clarify the mechanism by molecular dynamics (MD) simulations. Initially, we simulated the molecular conformations of KS-58 in water (a polar solvent) and in chloroform (a non-polar solvent). The identified stable conformations were significantly different in each solvent. KS-58 behaves as a chameleon-like molecule as it alters its polar surface area (PSA) depending on the solvent environment. It was also discovered that orientation of Asp's side chain is a critical energy barrier for KS-58 altering its conformation from hydrophilic to lipophilic. Taking these properties into consideration, we simulated its lipid bilayer membrane permeability. KS-58 shifted toward the inside of the lipid bilayer membrane with altering its conformations to lipophilic. When the simulation condition was set in deionized form of that carboxy group of Asp, KS-58 traveled deeper inside the cell membrane. PSA and the depth of the membrane penetration correlated. In vitro data suggested that cell membrane permeability of KS-58 is improved in weakly acidic conditions leading to partial deionization of the carboxy group. Our data provide an example of the molecular properties of mid-size peptides with membrane accessibility and propose an effective metadynamics approach to elucidate such molecular mechanisms by MD simulations.
    Keywords:  Chameleon-like molecule; Conformational changes; Cyclic peptide; KS-58; Membrane permeability; Mid-size peptide
    DOI:  https://doi.org/10.1016/j.bmcl.2024.129649
  3. Chem Sci. 2024 Feb 14. 15(7): 2300-2322
    Biocompatible strategies for peptide macrocyclisation.
    Junming He, Pritha Ghosh, Christoph Nitsche.
      Peptides are increasingly important drug candidates, offering numerous advantages over conventional small molecules. However, they face significant challenges related to stability, cellular uptake and overall bioavailability. While individual modifications may not address all these challenges, macrocyclisation stands out as a single modification capable of enhancing affinity, selectivity, proteolytic stability and membrane permeability. The recent successes of in situ peptide modifications during screening in combination with genetically encoded peptide libraries have increased the demand for peptide macrocyclisation reactions that can occur under biocompatible conditions. In this perspective, we aim to distinguish biocompatible conditions from those well-known examples that are fully bioorthogonal. We introduce key strategies for biocompatible peptide macrocyclisation and contextualise them within contemporary screening methods, providing an overview of available transformations.
    DOI:  https://doi.org/10.1039/d3sc05738k
  4. PLoS One. 2024 ;19(2): e0293072
    Discovery and characterization of anti-cancer peptides from a random peptide library.
    Pavan Kumar Puvvula, Anne M Moon.
      We performed a forward genetic screen to discover peptides that specifically target breast cancer cells using a Penetratin tagged, random 15mer peptide library. We identified a group of novel peptides that specifically inhibited the proliferation and survival of breast cancer cells without affecting normal primary mammary epithelial cells or fibroblasts. The intrinsic apoptotic pathway is activated by these peptides in the face of abnormal expression of numerous cell cycle regulatory genes. Associated alterations in histone marks, nuclear structure, and levels of critical RNA binding proteins vary in a peptide specific manner. This study demonstrates a novel method for the discovery of new potential therapeutic peptides.
    DOI:  https://doi.org/10.1371/journal.pone.0293072
  5. Transl Oncol. 2024 Feb 14. pii: S1936-5233(24)00018-4. [Epub ahead of print]42 101892
    Peptide-based inhibitors targeting the PD-1/PD-L1 axis: potential immunotherapeutics for cancer.
    Magdalena Bojko, Katarzyna Węgrzyn, Emilia Sikorska, Piotr Ciura, Claire Battin, Peter Steinberger, Katarzyna Magiera-Mularz, Grzegorz Dubin, Adam Kulesza, Adam K Sieradzan, Marta Spodzieja, Sylwia Rodziewicz-Motowidło.
      The PD-1/PD-L1 complex belongs to the group of inhibitory immune checkpoints and plays a critical role in immune regulation. The PD-1/PD-L1 axis is also responsible for immune evasion of cancer cells, and this complex is one of the main targets of immunotherapies used in oncology. Treatment using immune checkpoint inhibitors is mainly based on antibodies. This approach has great therapeutic potential; however, it also has major drawbacks and can induce immune-related adverse events. Thus, there is a strong need for alternative, non-antibody-based therapies using small molecules, peptides, or peptidomimetics. In the present study, we designed, synthesized, and evaluated a set of PD-1-targeting peptides based on the sequence and structure of PD-L1. The binding of these peptides to PD-1 was investigated using SPR and ELISA. We also assessed their ability to compete with PD-L1 for binding to PD-1 and their inhibitory properties against the PD-1/PD-L1 complex at the cellular level. The best results were obtained for the peptide PD-L1(111-127)(Y112C-I126C), named (L11), which displaced PD-L1 from binding to PD-1 in the competitive assay and inhibited the formation of the PD-1/PD-L1 complex. The (L11) peptide also exhibited strong affinity for PD-1. NMR studies revealed that (L11) does not form a well-defined secondary structure; however, MD simulation indicated that (L11) binds to PD-1 at the same place as PD-L1. After further optimization of the structure, the peptide inhibitor obtained in this study could also be used as a potential therapeutic compound targeting the PD-1/PD-L1 axis.
    Keywords:  Cancer; Disulfide-linked peptide; Immune checkpoint inhibitor; Immunotherapy; PD-1 - Programmed cell death 1; PD-L1 - Programmed cell death 1 - ligand 1
    DOI:  https://doi.org/10.1016/j.tranon.2024.101892
  6. J Chem Inf Model. 2024 Feb 14.
    Structure-Guided Discovery of PD-1/PD-L1 Interaction Inhibitors: Peptide Design, Screening, and Optimization via Computation-Aided Phage Display Engineering.
    Tien-Sheng Tseng, Chao-Chang Lee, Po-Juei Chen, Chiu-Yuen Lin, Wang-Chuan Chen, Yu-Ching Lee, Jiun-Han Lin, Kaun-Wen Chen, Keng-Chang Tsai.
      Cancer immunotherapy harnesses the immune system to combat tumors and has emerged as a major cancer treatment modality. The PD-1/PD-L1 immune checkpoint modulates interactions between tumor cells and T cells and has been extensively targeted in cancer immunotherapy. However, the monoclonal antibodies known to target this immune checkpoint have considerable side effects, and novel PD-1/PD-L1 inhibitors are therefore required. Herein, a peptide inhibitor to disrupt PD-1/PD-L1 interactions was designed through structure-driven phage display engineering coupled to computational modification and optimization. BetaPb, a novel peptide library constructed by using the known structure of PD-1/PD-L, was used to develop inhibitors against the immune checkpoint, and specific peptides with high affinity toward PD-1 were screened through enzyme-linked immunosorbent assays, homogeneous time-resolved fluorescence, and biolayer interferometry. A potential inhibitor, B8, was preliminarily screened through biopanning. The binding affinity of B8 toward PD-1 was confirmed through computation-aided optimization. Assessment of B8 variants (B8.1, B8.2, B8.3, B8.4, and B8.5) demonstrated their attenuation of PD-1/PD-L1 interactions. B8.4 exhibited the strongest attenuation efficiency at a half-maximal effective concentration of 0.1 μM and the strongest binding affinity to PD-1 (equilibrium dissociation constant = 0.1 μM). B8.4 outperformed the known PD-1/PD-L1 interaction inhibitor PL120131 in disrupting PD-1/PD-L1 interactions, revealing that B8.4 has remarkable potential for modification to yield an antitumor agent. This study provides valuable information for the future development of peptide-based drugs, therapeutics, and immunotherapies for cancer.
    DOI:  https://doi.org/10.1021/acs.jcim.3c01500
  7. Curr Med Chem. 2024 Feb 15.
    Cell-Penetrating Peptides as Keys to Endosomal Escape and Intracellular Trafficking in Nanomedicine Delivery.
    Sakshi Soni, Shivam K Kori, Priyanshu Nema, Arun K Iyer, Vandana Soni, Sushil K Kashaw.
      This review article discusses the challenges of delivering cargoes to the cytoplasm, for example, proteins, peptides, and nucleic acids, and the mechanisms involved in endosomal escape. Endocytosis, endosomal maturation, and exocytosis pose significant barriers to effective cytoplasmic delivery. The article explores various endosomal escape mechanisms, such as the proton sponge effect, osmotic lysis, membrane fusion, pore formation, membrane destabilization/ disruption, and vesicle budding and collapse. Additionally, it discusses the role of lysosomes, glycocalyx, and molecular crowding in the cytoplasmic delivery process. Despite the recent advances in nonviral delivery systems, there is still a need to improve cytoplasmic delivery. Strategies such as fusogenic peptides, endosomolytic polymers, and cell-penetrating peptides have shown promise in improving endosomal escape and cytoplasmic delivery. More research is needed to refine these strategies and make them safer and more effective. In conclusion, the article highlights the challenges associated with cytoplasmic delivery and the importance of understanding the mechanisms involved in endosomal escape. A better understanding of these processes could result in the creation of greater effectiveness and safe delivery systems for various cargoes, including proteins, peptides, and nucleic acids.
    Keywords:  Endosomal escape; Nanoparticle delivery; Cytoplasmic trafficking; siRNA; Non-viral vectors; Membrane fusion; Lysosome
    DOI:  https://doi.org/10.2174/0109298673278936240107121907
  8. ACS Nano. 2024 Feb 12.
    An Endosomal Escape Trojan Horse Platform to Improve Cytosolic Delivery of Nucleic Acids.
    Steven Narum, Brendan Deal, Hiroaki Ogasawara, Joseph Nicholas Mancuso, Jiahui Zhang, Khalid Salaita.
      Endocytosis is a major bottleneck toward cytosolic delivery of nucleic acids, as the vast majority of nucleic acid drugs remain trapped within endosomes. Current trends to overcome endosomal entrapment and subsequent degradation provide varied success; however, active delivery agents such as cell-penetrating peptides have emerged as a prominent strategy to improve cytosolic delivery. Yet, these membrane-active agents have poor selectivity for endosomal membranes, leading to toxicity. A hallmark of endosomes is their acidic environment, which aids in degradation of foreign materials. Here, we develop a pH-triggered spherical nucleic acid that provides smart antisense oligonucleotide (ASO) release upon endosomal acidification and selective membrane disruption, termed DNA EndosomaL Escape Vehicle Response (DELVR). We anchor i-Motif DNA to a nanoparticle (AuNP), where the complement strand contains both an ASO sequence and a functionalized endosomal escape peptide (EEP). By orienting the EEP toward the AuNP core, the EEP is inactive until it is released through acidification-induced i-Motif folding. In this study, we characterize a small library of i-Motif duplexes to develop a structure-switching nucleic acid sequence triggered by endosomal acidification. We evaluate antisense efficacy using HIF1a, a hypoxic indicator upregulated in many cancers, and demonstrate dose-dependent activity through RT-qPCR. We show that DELVR significantly improves ASO efficacy in vitro. Finally, we use fluorescence lifetime imaging and activity measurement to show that DELVR benefits synergistically from nuclease- and pH-driven release strategies with increased ASO endosomal escape efficiency. Overall, this study develops a modular platform that improves the cytosolic delivery of nucleic acid therapeutics and offers key insights for overcoming intracellular barriers.
    Keywords:  HIF1a; antisense therapy; endosomal escape; i-Motif; nanomedicine; nucleic acid delivery
    DOI:  https://doi.org/10.1021/acsnano.3c09027
  9. Biophys J. 2024 Feb 14. pii: S0006-3495(24)00105-X. [Epub ahead of print]
    Peptide Translocation Across Asymmetric Phospholipid Membranes.
    Ladislav Bartoš, Robert Vácha.
      The transport of molecules across cell membranes is vital for proper cell function and effective drug delivery. While most cell membranes naturally possess an asymmetric lipid composition, research on membrane transport predominantly uses symmetric lipid membranes. The permeation through asymmetric membrane is then calculated as a sum of the inverse permeabilities of leaflets from symmetric bilayers. In this study, we examined how two types of amphiphilic molecules translocate across both asymmetric and symmetric membranes. Using computer simulations with both coarse-grained and atomistic force fields, we calculated the free energy profiles for the passage of model amphiphilic peptides and a lipid across various membranes. Our results consistently demonstrate that while the free energy profiles for asymmetric membranes with a small differential stress concur with symmetric ones in the region of lipid headgroups, the profiles differ around the center of the membrane. In this region, the free energy for the asymmetric membrane transitions between the profiles for two symmetric membranes. In addition, we show that peptide permeability through an asymmetric membrane cannot always be predicted from the permeabilities of the symmetric membranes. This indicates that using symmetric membranes falls short in providing an accurate depiction of peptide translocation across asymmetric membranes.
    DOI:  https://doi.org/10.1016/j.bpj.2024.02.006
  10. J Med Chem. 2024 Feb 12.
    Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design.
    Luis E Gimenez, Charlotte Martin, Jing Yu, Charlie Hollanders, Ciria C Hernandez, Yiran Wu, Deqiang Yao, Gye Won Han, Naima S Dahir, Lijie Wu, Olivier Van der Poorten, Arthur Lamouroux, Morgane Mannes, Suwen Zhao, Dirk Tourwé, Raymond C Stevens, Roger D Cone, Steven Ballet.
      Melanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with PG-934 and SBL-MC-31. These peptides differ from SHU9119 by substituting His6 with Pro6 and inserting Gly10 or Arg10. The structures revealed two subpockets at the TM7-TM1-TM2 domains, separated by N2857.36. Two peptide series based on the complexed peptides led to an antagonist activity and selectivity SAR study. Most ligands retained the SHU9119 potency, but several SBL-MC-31-derived peptides significantly enhanced MC4-R selectivity over MC1-R by 60- to 132-fold. We also investigated MC4-R coupling to the K+ channel, Kir7.1. Some peptides activated the channel, whereas others induced channel closure independently of G protein coupling. In cell culture studies, channel activation correlated with increased feeding, while a peptide with Kir7.1 inhibitory activity reduced eating. These results highlight the potential for targeting the MC4-R:Kir7.1 complex for treating positive and restrictive eating disorders.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c01822
  11. Curr Cancer Drug Targets. 2024 Feb 13.
    Stabilizing Scaffold for Short Peptides Based on Knottins.
    Evgenii Beloborodov, Elena Iurova, Dmitrii Sugak, Eugenia Rastorgueva, Evgeniya Pogodina, Aleksandr Fomin, Denis Viktorov, Sergei Slesarev, Yury Saenko.
       BACKGROUND: Bombesin (BBN) is a short peptide with a high affinity for receptors that are expressed on the surface of various types of cancer cells. However, a full length BBN molecule has low in vivo stability.
    OBJECTIVE: In our study, we propose the use of peptide toxins, derived from animal and plant toxins, as scaffold molecules to enhance the bioavailability and stability of bombesin. These peptides possess a unique structure known as an inhibitory cystine knot.
    METHODS: We synthesized structures in which short bombesin was incorporated into various domains of arthropod and plant toxins using solid-phase peptide synthesis. The stability under different conditions was assessed through high-performance liquid chromatography, and binding to cell cultures expressing the bombesin receptor was analyzed. Additionally, toxicity to cell cultures was evaluated using fluorescence microscopy.
    RESULTS: The data obtained demonstrated that placing the short peptide between the first and second cysteine residues in arachnid toxins results in increased in vitro stability and bioavailability, as well as low cytotoxicity.
    CONCLUSION: Arachnid toxins with an inhibitory cystine knot can be considered as a scaffold for increasing the stability of therapeutic peptides.
    Keywords:  bombesin; cancer.; inhibitory cystine knot; peptide toxin; stability
    DOI:  https://doi.org/10.2174/0115680096285288240118090050
  12. J Cell Biochem. 2024 Feb 16.
    Induction of stearoyl-CoA desaturase confers cell density-dependent ferroptosis resistance in melanoma.
    Hitomi Shirahama, Yuri Tani, Satomi Tsukahara, Yuka Okamoto, Akiko Hasebe, Tomomiki Noda, Shuji Ando, Masaru Ushijima, Masaaki Matsuura, Akihiro Tomida.
      Ferroptosis is a form of regulated cell death that is induced by inhibiting glutathione peroxidase 4 (GPX4), which eliminates lipid peroxidation. Ferroptosis induction is influenced by the cell environment. However, the cellular states altering ferroptosis susceptibility remain largely unknown. We found that melanoma cell lines became resistant to ferroptosis as cell density increased. Comparative transcriptome and metabolome analyses revealed that cell density-dependent ferroptosis resistance was coupled with a shift toward a lipogenic phenotype accompanied by strong induction of stearoyl-CoA desaturase (SCD). Database analysis of gene dependency across hundreds of cancer cell lines uncovered a negative correlation between GPX4 and SCD dependency. Importantly, SCD inhibition, either pharmacologically or through genetic knockout, sensitized melanoma cells to GPX4 inhibition, thereby attenuating ferroptosis resistance in cells at high density. Our findings indicate that transition to an SCD-inducing, lipogenic cell state produces density-dependent resistance to ferroptosis, which may provide a therapeutic strategy against melanoma.
    Keywords:  ferroptosis; glutathione peroxidase 4; melanoma; stearoyl-CoA desaturase
    DOI:  https://doi.org/10.1002/jcb.30542
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