bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–03–03
nine papers selected by
Henry Lamb, Queensland University of Technology
  1. Uptake pathways of cell-penetrating peptides in the context of drug delivery, gene therapy, and vaccine development.
  2. Cytosolic Delivery of Bioactive Cyclic Peptide Cargo by Spontaneous Membrane Translocating Peptides.
  3. DexDesign: A new OSPREY-based algorithm for designing de novo D-peptide inhibitors.
  4. Peptide-Drug Conjugate with Statistically Designed Transcellular Peptide for Psoriasis-Like Inflammation.
  5. Exponential Combination of a and e/g Intracellular Peptide Libraries Identifies a Selective ATF3 Inhibitor.
  6. Macrocycles and macrocyclization in anticancer drug discovery: Important pieces of the puzzle.
  7. Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins.
  8. Modular tissue-in-a-CUBE platform to model blood-brain barrier (BBB) and brain interaction.
  9. Peptide-Directed Attachment of Hydroxylamines to Specific Lysines of IgG Antibodies for Bioconjugations with Acylboronates.
  1. Cell Signal. 2024 Feb 24. pii: S0898-6568(24)00084-6. [Epub ahead of print]117 111116
    Uptake pathways of cell-penetrating peptides in the context of drug delivery, gene therapy, and vaccine development.
    Moataz Dowaidar.
      Cell-penetrating peptides have been extensively utilized for the purpose of facilitating the intracellular delivery of cargo that is impermeable to the cell membrane. The researchers have exhibited proficient delivery capabilities for oligonucleotides, thereby establishing cell-penetrating peptides as a potent instrument in the field of gene therapy. Furthermore, they have demonstrated a high level of efficiency in delivering several additional payloads. Cell penetrating peptides (CPPs) possess the capability to efficiently transport therapeutic molecules to specific cells, hence offering potential remedies for many illnesses. Hence, their utilization is imperative for the improvement of therapeutic vaccines. In contemporary studies, a plethora of cell-penetrating peptides have been unveiled, each characterized by its own distinct structural attributes and associated mechanisms. Although it is widely acknowledged that there are multiple pathways through which particles might be internalized, a comprehensive understanding of the specific mechanisms by which these particles enter cells has to be fully elucidated. The absorption of cell-penetrating peptides can occur through either direct translocation or endocytosis. However, it is worth noting that categories of cell-penetrating peptides are not commonly linked to specific entrance mechanisms. Furthermore, research has demonstrated that cell-penetrating peptides (CPPs) possess the capacity to enhance antigen uptake by cells and facilitate the traversal of various biological barriers. The primary objective of this work is to examine the mechanisms by which cell-penetrating peptides are internalized by cells and their significance in facilitating the administration of drugs, particularly in the context of gene therapy and vaccine development. The current study investigates the immunostimulatory properties of numerous vaccine components administered using different cell-penetrating peptides (CPPs). This study encompassed a comprehensive discussion on various topics, including the uptake pathways and mechanisms of cell-penetrating peptides (CPPs), the utilization of CPPs as innovative vectors for gene therapy, the role of CPPs in vaccine development, and the potential of CPPs for antigen delivery in the context of vaccine development.
    Keywords:  Antigen; Antigen-Presenting Cell (APC); CPPs; Cell-penetrating peptides; Drug delivery; Gene therapy; Pathways/mechanism; Trans-Activator of Transcription (TAT); Vaccine development
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111116
  2. ACS Omega. 2024 Feb 20. 9(7): 8179-8187
    Cytosolic Delivery of Bioactive Cyclic Peptide Cargo by Spontaneous Membrane Translocating Peptides.
    Ryan P Ferrie, Taylor Fuselier, William C Wimley.
      Cyclic peptides that inhibit protein-protein interactions have significant advantages over linear peptides and small molecules for modulating cellular signaling networks in cancer and other diseases. However, the permeability barrier of the plasma membrane remains a formidable obstacle to the development of cyclic peptides into applicable drugs. Here, we test the ability of a family of synthetically evolved spontaneous membrane translocating peptides (SMTPs) to deliver phalloidin, a representative bioactive cyclic peptide, to the cytosol of human cells in culture. Phalloidin does not enter cells spontaneously, but if delivered to the cytosol, it inhibits actin depolymerization. We thus use a wound-healing cell mobility assay to assess the biological activity of phalloidin conjugated to three SMTPs that we previously discovered. All three SMTPs can deliver phalloidin to the cell cytosol, and one does so at concentrations as low as 3 μM. Delivery occurs despite the fact that the SMTPs were originally selected based on membrane translocation with no cargo other than a small fluorescent dye. These results show that SMTPs are viable delivery vehicles for cyclic peptides, although their efficiency is moderate. Further, these results suggest that one additional generation of synthetic molecular evolution could be used to optimize SMTPs for the efficient delivery of any bioactive cyclic peptide into cells.
    DOI:  https://doi.org/10.1021/acsomega.3c08701
  3. bioRxiv. 2024 Feb 14. pii: 2024.02.12.579944. [Epub ahead of print]
    DexDesign: A new OSPREY-based algorithm for designing de novo D-peptide inhibitors.
    Nathan Guerin, Henry Childs, Pei Zhou, Bruce R Donald.
      With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan, which enable exponential reductions in the size of the peptide sequence search space. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a new framework for analyzing de novo peptides-evaluation along a replication/restitution axis-and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets' endogenous ligands, validating the peptides' potential as lead therapeutic candidates. We provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.
    DOI:  https://doi.org/10.1101/2024.02.12.579944
  4. Adv Healthc Mater. 2024 Feb 29. e2303480
    Peptide-Drug Conjugate with Statistically Designed Transcellular Peptide for Psoriasis-Like Inflammation.
    Do Hyun Bae, Hayeon Bae, Hyung-Seok Yu, Banzrach Dorsembe, Young Hyun No, Taejung Kim, Nam Hyeong Kim, Jinwoo Kim, Jiyool Kim, Bok-Soo Lee, Ye Ji Kim, Seongchan Park, Zinah Hilal Khaleel, Deok Hyang Sa, Eui-Chul Lee, Jaecheol Lee, Jungyeob Ham, Jin-Chul Kim, Yong Ho Kim.
      Peptide-drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems, including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, we employ physicochemical criteria based on cell penetrating peptides (CPPs) to design transcellular peptides derived from an antimicrobial peptides (AMPs) library. Among those the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, we find that 6-Paradol (PAR) exhibited inhibitory activity against phosphodiesterase 4 (PDE4), which can be utilized for an anti-inflammatory PDC. The transcellular PDC (SDT7-conjugated with PAR, named as TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular peptide-drug conjugates (TDCs) as a promising approach for the treatment of inflammatory skin disorders. This article is protected by copyright. All rights reserved.
    Keywords:  anti-inflammation; ginger driven compounds; peptide-drug conjugates; skin barrier; transcellular peptide
    DOI:  https://doi.org/10.1002/adhm.202303480
  5. ACS Chem Biol. 2024 Feb 27.
    Exponential Combination of a and e/g Intracellular Peptide Libraries Identifies a Selective ATF3 Inhibitor.
    Miao Yu, T M Simon Tang, Lila Ghamsari, Graham Yuen, Claudio Scuoppo, Jim A Rotolo, Barry J Kappel, Jody M Mason.
      Activating transcription factor 3 (ATF3) is an activation transcription factor/cyclic adenosine monophosphate (cAMP) responsive element-binding (CREB) protein family member. It is recognized as an important regulator of cancer progression by repressing expression of key inflammatory factors such as interferon-γ and chemokine (C-C motif) ligand 4 (CCL4). Here, we describe a novel library screening approach that probes individual leucine zipper components before combining them to search exponentially larger sequence spaces not normally accessible to intracellular screening. To do so, we employ two individual semirational library design approaches and screen using a protein-fragment complementation assay (PCA). First, a 248,832-member library explored 12 amino acid positions at all five a positions to identify those that provided improved binding, with all e/g positions fixed as Q, placing selection pressure onto the library options provided. Next, a 59,049-member library probed all ten e/g positions with 3 options. Similarly, during e/g library screening, a positions were locked into a generically bindable sequence pattern (AIAIA), weakly favoring leucine zipper formation, while placing selection pressure onto e/g options provided. The combined a/e/g library represents ∼14.7 billion members, with the resulting peptide, ATF3W_aeg, binding ATF3 with high affinity (Tm = 60 °C; Kd = 151 nM) while strongly disfavoring homodimerization. Moreover, ATF3W_aeg is notably improved over component PCA hits, with target specificity found to be driven predominantly by electrostatic interactions. The combined a/e/g exponential library screening approach provides a robust, accelerated platform for exploring larger peptide libraries, toward derivation of potent yet selective antagonists that avoid homoassociation to provide new insight into rational peptide design.
    DOI:  https://doi.org/10.1021/acschembio.3c00779
  6. Eur J Med Chem. 2024 Feb 13. pii: S0223-5234(24)00114-4. [Epub ahead of print]268 116234
    Macrocycles and macrocyclization in anticancer drug discovery: Important pieces of the puzzle.
    Chao Zhang, Fenfen Liu, Youming Zhang, Chun Song.
      Increasing disease-related proteins have been identified as novel therapeutic targets. Macrocycles are emerging as potential solutions, bridging the gap between conventional small molecules and biomacromolecules in drug discovery. Inspired by successful macrocyclic drugs of natural origins, macrocycles are attracting more attention for enhanced binding affinity and target selectivity. Due to the conformation constraint and structure preorganization, macrocycles can reach bioactive conformations more easily than parent acyclic compounds. Also, rational macrocyclization combined with sequent structural modification will help improve oral bioavailability and combat drug resistance. This review introduces various strategies to enhance membrane permeability in macrocyclization and subsequent modification, such as N-methylation, intramolecular hydrogen bonding modulation, isomerization, and reversible bicyclization. Several case studies highlight macrocyclic inhibitors targeting kinases, HDAC, and protein-protein interactions. Finally, some macrocyclic agents targeting tumor microenvironments are illustrated.
    Keywords:  Anticancer drug discovery; Binding affinity; Cell penetration; Macrocycle; Target selectivity
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116234
  7. Nat Commun. 2024 Feb 28. 15(1): 1813
    Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins.
    Alex J Callahan, Satish Gandhesiri, Tara L Travaline, Rahi M Reja, Lia Lozano Salazar, Stephanie Hanna, Yen-Chun Lee, Kunhua Li, Olena S Tokareva, Jean-Marie Swiecicki, Andrei Loas, Gregory L Verdine, John H McGee, Bradley L Pentelute.
      Widespread adoption of mirror-image biological systems presents difficulties in accessing the requisite D-protein substrates. In particular, mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders with potentially unique recognition modes but is hindered by the individualized optimization required for D-protein chemical synthesis. We demonstrate a general mirror-image phage display pipeline that utilizes automated flow peptide synthesis to prepare D-proteins in a single run. With this approach, we prepare and characterize 12 D-proteins - almost one third of all reported D-proteins to date. With access to mirror-image protein targets, we describe the successful discovery of six macrocyclic D-peptide binders: three to the oncoprotein MDM2, and three to the E3 ubiquitin ligase CHIP. Reliable production of mirror-image proteins can unlock the full potential of D-peptide drug discovery and streamline the study of mirror-image biology more broadly.
    DOI:  https://doi.org/10.1038/s41467-024-45634-z
  8. Commun Biol. 2024 Feb 28. 7(1): 177
    Modular tissue-in-a-CUBE platform to model blood-brain barrier (BBB) and brain interaction.
    Isabel Koh, Masaya Hagiwara.
      With the advent of increasingly sophisticated organoids, there is growing demand for technology to replicate the interactions between multiple tissues or organs. This is challenging to achieve, however, due to the varying culture conditions of the different cell types that make up each tissue. Current methods often require complicated microfluidic setups, but fragile tissue samples tend not to fare well with rough handling. Furthermore, the more complicated the human system to be replicated, the more difficult the model becomes to operate. Here, we present the development of a multi-tissue chip platform that takes advantage of the modularity and convenient handling ability of a CUBE device. We first developed a blood-brain barrier-in-a-CUBE by layering astrocytes, pericytes, and brain microvascular endothelial cells in the CUBE, and confirmed the expression and function of important tight junction and transporter proteins in the blood-brain barrier model. Then, we demonstrated the application of integrating Tissue-in-a-CUBE with a chip in simulating the in vitro testing of the permeability of a drug through the blood-brain barrier to the brain and its effect on treating the glioblastoma brain cancer model. We anticipate that this platform can be adapted for use with organoids to build complex human systems in vitro by the combination of multiple simple CUBE units.
    DOI:  https://doi.org/10.1038/s42003-024-05857-8
  9. Angew Chem Int Ed Engl. 2024 Feb 29. e202401080
    Peptide-Directed Attachment of Hydroxylamines to Specific Lysines of IgG Antibodies for Bioconjugations with Acylboronates.
    Matthias Tanriver, Marco Müller, Mikai D Levasseur, Daniel Richards, Sohei Majima, Andew DeMello, Yohei Yamauchi, Jeffrey W Bode.
      The role of monoclonal antibodies as vehicles to deliver payloads has evolved as a powerful tool in cancer therapy in recent years. The clinical development of therapeutic antibody-conjugates with precise payloads holds great promise for targeted therapeutic interventions. The use of affinity-peptide mediated functionalization of native off-the-shelf antibodies offers an effective approach to selectively modify IgG antibodies with a drug antibody ratio (DAR) of 2. Here, we report the traceless, peptide-directed attachment of two hydroxylamines to native IgGs followed by chemoselective potassium acyltrifluboroborate (KA) ligation with quinolinium acyltrifluoroborates (QATs), which provide enhanced ligation rates with hydroxylamines under physiological conditions. By applying KAT ligation to the modified antibodies, conjugation of small molecules, proteins, and oligonucleotides to off-the-shelf IgGs proceeds efficiently, in good yields, and with simultaneous cleavage of the affinity peptide-directing moiety.
    Keywords:  Antibodies Affinity peptide Bioonjugation Antibody-drug conjugate KAT Ligation
    DOI:  https://doi.org/10.1002/anie.202401080
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