bims-cepepe 2023-12-17 papers

bims-cepepe

Biomed News

on Cell-penetrating peptides

Issue of 2023–12–17
ten papers selected by
Henry Lamb, Queensland University of Technology

Recent Uses of Lipid Nanoparticles, Cell-Penetrating and Bioactive Peptides for the Development of Brain-Targeted Nanomedicines against Neurodegenerative Disorders.
Retraction: The Rational Design of Specific Peptide Inhibitor against p38α MAPK at Allosteric-Site: A Therapeutic Modality for HNSCC.
Enhancing the Antimicrobial Properties of Peptides through Cell-Penetrating Peptide Conjugation: A Comprehensive Assessment.
Development of PD-1 blockade peptide-cell conjugates to enhance cellular therapies for T-cell acute lymphoblastic leukemia.
Brain-Penetrating Peptide Shuttles across the Blood-Brain Barrier and Extracellular-like Space.
Irreversible inhibition of TRF2TRFH recruiting functions by a covalent cyclic peptide induces telomeric replication stress in cancer cells.
Conformations of Macrocyclic Peptides Sampled by Nuclear Magnetic Resonance: Models for Cell-Permeability.
De Novo Discovery of Cysteine Frameworks for Developing Multicyclic Peptide Libraries for Ligand Discovery.
Antimicrobial Peptide-Peptoid Hybrids with and without Membrane Disruption.
Acid-sensing ion channel 1a blockade reduces myocardial injury in rodent models of myocardial infarction.

Nanomaterials (Basel). 2023 Nov 23. pii: 3004. [Epub ahead of print]13(23):

Recent Uses of Lipid Nanoparticles, Cell-Penetrating and Bioactive Peptides for the Development of Brain-Targeted Nanomedicines against Neurodegenerative Disorders.

Yu Wu, Angelina Angelova.

  The lack of effective treatments for neurodegenerative diseases (NDs) is an important current concern. Lipid nanoparticles can deliver innovative combinations of active molecules to target the various mechanisms of neurodegeneration. A significant challenge in delivering drugs to the brain for ND treatment is associated with the blood-brain barrier, which limits the effectiveness of conventional drug administration. Current strategies utilizing lipid nanoparticles and cell-penetrating peptides, characterized by various uptake mechanisms, have the potential to extend the residence time and bioavailability of encapsulated drugs. Additionally, bioactive molecules with neurotropic or neuroprotective properties can be delivered to potentially mediate the ND targeting pathways, e.g., neurotrophin deficiency, impaired lipid metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, accumulation of misfolded proteins or peptide fragments, toxic protein aggregates, oxidative stress damage, and neuroinflammation. This review discusses recent advancements in lipid nanoparticles and CPPs in view of the integration of these two approaches into nanomedicine development and dual-targeted nanoparticulate systems for brain delivery in neurodegenerative disorders.

Keywords:  CPP-functionalized particles; cell-penetrating peptide (CPP); cubosomes; lipid nanoparticles; liquid crystalline nanocarriers; nanomedicine; neuroprotection; pituitary adenylate cyclase-activating polypeptide (PACAP)

DOI:  https://doi.org/10.3390/nano13233004
PLoS One. 2023 ;18(12): e0295637

Retraction: The Rational Design of Specific Peptide Inhibitor against p38α MAPK at Allosteric-Site: A Therapeutic Modality for HNSCC.

PLOS ONE Editors

DOI: https://doi.org/10.1371/journal.pone.0295637
Int J Mol Sci. 2023 Nov 24. pii: 16723. [Epub ahead of print]24(23):

Enhancing the Antimicrobial Properties of Peptides through Cell-Penetrating Peptide Conjugation: A Comprehensive Assessment.

Sergey V Kravchenko, Pavel A Domnin, Sergei Y Grishin, Nikita A Vershinin, Elena V Gurina, Anastasiia A Zakharova, Viacheslav N Azev, Leila G Mustaeva, Elena Y Gorbunova, Margarita I Kobyakova, Alexey K Surin, Roman S Fadeev, Olga S Ostroumova, Svetlana A Ermolaeva, Oxana V Galzitskaya.

  Combining antimicrobial peptides (AMPs) with cell-penetrating peptides (CPPs) has shown promise in boosting antimicrobial potency, especially against Gram-negative bacteria. We examined the CPP-AMP interaction with distinct bacterial types based on cell wall differences. Our investigation focused on AMPs incorporating penetratin CPP and dihybrid peptides containing both cell-penetrating TAT protein fragments from the human immunodeficiency virus and Antennapedia peptide (Antp). Assessment of the peptides TAT-AMP, AMP-Antp, and TAT-AMP-Antp revealed their potential against Gram-positive strains (Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), and Bacillus cereus). Peptides TAT-AMP and AMP-Antp using an amyloidogenic AMP from S1 ribosomal protein Thermus thermophilus, at concentrations ranging from 3 to 12 μM, exhibited enhanced antimicrobial activity against B. cereus. TAT-AMP and TAT-AMP-Antp, using an amyloidogenic AMP from the S1 ribosomal protein Pseudomonas aeruginosa, at a concentration of 12 µM, demonstrated potent antimicrobial activity against S. aureus and MRSA. Notably, the TAT-AMP, at a concentration of 12 µM, effectively inhibited Escherichia coli (E. coli) growth and displayed antimicrobial effects similar to gentamicin after 15 h of incubation. Peptide characteristics determined antimicrobial activity against diverse strains. The study highlights the intricate relationship between peptide properties and antimicrobial potential. Mechanisms of AMP action are closely tied to bacterial cell wall attributes. Peptides with the TAT fragment exhibited enhanced antimicrobial activity against S. aureus, MRSA, and P. aeruginosa. Peptides containing only the Antp fragment displayed lower activity. None of the investigated peptides demonstrated cytotoxic or cytostatic effects on either BT-474 cells or human skin fibroblasts. In conclusion, CPP-AMPs offer promise against various bacterial strains, offering insights for targeted antimicrobial development.

Keywords:  Antennapedia peptide; FoldAmyloid; TAT fragment; amyloid; antimicrobial peptides; cell-penetrating peptide; ribosomal S1 protein

DOI:  https://doi.org/10.3390/ijms242316723
Med Oncol. 2023 Dec 11. 41(1): 14

Development of PD-1 blockade peptide-cell conjugates to enhance cellular therapies for T-cell acute lymphoblastic leukemia.

Quanxiao Wang, Hongxing Huang, Peisheng Liang, Lili Wang, Junheng Zheng, Yan Zhang, Hua Wang.

  Blockade of the interaction of the immune checkpoint receptor programmed cell death protein (PD)-1 and its ligand PD-L1 has been found to be a promising cancer treatment. Our previous studies identified that nABPD1 competed with PD-L1 to bind PD-1. The aim of this study was to evaluate the efficacy and safety of anti-tumor immunotherapy of ICIK cells conjugated with peptides in vivo and in vitro. Here, we synthesized the nABPD1 derivatives SBP1 and SBP2 and showed that their binding efficiency to PD-1-positive improving cytokine-induced killer (ICIK) cells was 98 and 82%, respectively. The cytotoxicity of ICIK cells to T-cell acute lymphoblastic leukemia (T-ALL) cells was increased by conjugating with SBP1 or SBP2, which was 2 times higher than that of ICIK cells alone. Furthermore, mice experiments showed that the fluorescence intensity of leukemia cells in T-ALL xenograft models was reduced by more than 95%, indicating that the peptides enhanced the therapeutic effect in vivo, while morphological evaluations showed that the peptides had no toxicity to important organs. Therefore, peptide-cell conjugates (PCCs) may be a novel method to improve the efficacy of cancer immunotherapy by blocking PD-1 in T-ALL patients.

Keywords:  ICIK; Immunotherapy; PCCs; PD-1 binding peptide; T-ALL

DOI:  https://doi.org/10.1007/s12032-023-02235-y
Bioconjug Chem. 2023 Dec 12.

Brain-Penetrating Peptide Shuttles across the Blood-Brain Barrier and Extracellular-like Space.

Xiujuan Peng, Xinquan Liu, Jae You Kim, Alex Nguyen, Jasmim Leal, Debadyuti Ghosh.

Systemic delivery of therapeutics into the brain is greatly impaired by multiple biological barriers─the blood-brain barrier (BBB) and the extracellular matrix (ECM) of the extracellular space. To address this problem, we developed a combinatorial approach to identify peptides that can shuttle and transport across both barriers. A cysteine-constrained heptapeptide M13 phage display library was iteratively panned against an established BBB model for three rounds to select for peptides that can transport across the barrier. Using next-generation DNA sequencing and in silico analysis, we identified peptides that were selectively enriched from successive rounds of panning for functional validation in vitro and in vivo. Select peptide-presenting phages exhibited efficient shuttling across the in vitro BBB model. Two clones, Pep-3 and Pep-9, exhibited higher specificity and efficiency of transcytosis than controls. We confirmed that peptides Pep-3 and Pep-9 demonstrated better diffusive transport through the extracellular matrix than gold standard nona-arginine and clinically trialed angiopep-2 peptides. In in vivo studies, we demonstrated that systemically administered Pep-3 and Pep-9 peptide-presenting phages penetrate the BBB and distribute into the brain parenchyma. In addition, free peptides Pep-3 and Pep-9 achieved higher accumulation in the brain than free angiopep-2 and may exhibit brain targeting. In summary, these in vitro and in vivo studies highlight that combinatorial phage display with a designed selection strategy can identify peptides as promising carriers, which are able to overcome the multiple biological barriers of the brain and shuttle different-sized molecules from small fluorophores to large macromolecules for improved delivery into the brain.

DOI: https://doi.org/10.1021/acs.bioconjchem.3c00446
Cell Chem Biol. 2023 Dec 06. pii: S2451-9456(23)00423-3. [Epub ahead of print]

Irreversible inhibition of TRF2TRFH recruiting functions by a covalent cyclic peptide induces telomeric replication stress in cancer cells.

Alexander P Sobinoff, Salvatore Di Maro, Ronnie R J Low, Rosaria Benedetti, Stefano Tomassi, Antonia D'Aniello, Rosita Russo, Ilaria Baglivo, Ugo Chianese, Paolo V Pedone, Angela Chambery, Anthony J Cesare, Lucia Altucci, Hilda A Pickett, Sandro Cosconati.

  The TRF2 shelterin component is an essential regulator of telomere homeostasis and genomic stability. Mutations in the TRF2TRFH domain physically impair t-loop formation and prevent the recruitment of several factors that promote efficient telomere replication, causing telomeric DNA damage. Here, we design, synthesize, and biologically test covalent cyclic peptides that irreversibly target the TRF2TRFH domain. We identify APOD53 as our most promising compound, as it consistently induces a telomeric DNA damage response in cancer cell lines. APOD53 forms a covalent adduct with a reactive cysteine residue present in the TRF2TRFH domain and induces phenotypes consistent with TRF2TRFH domain mutants. These include induction of a telomeric DNA damage response, increased telomeric replication stress, and impaired recruitment of RTEL1 and SLX4 to telomeres. We demonstrate that APOD53 impairs cancer cell growth and find that co-treatment with APOD53 can exacerbate telomere replication stress caused by the G4 stabilizer RHPS4 and low dose aphidicolin (APH).

Keywords:  RTEL1; SLX4; TRF2; covalent binder; cyclic peptides; replication stress; shelterin; telomere

DOI:  https://doi.org/10.1016/j.chembiol.2023.11.008
J Am Chem Soc. 2023 Dec 07.

Conformations of Macrocyclic Peptides Sampled by Nuclear Magnetic Resonance: Models for Cell-Permeability.

Simon H Rüdisser, Emmanuel Matabaro, Lukas Sonderegger, Peter Güntert, Markus Künzler, Alvar D Gossert.

The biological activities and pharmacological properties of peptides and peptide mimetics are determined by their conformational states. Therefore, a detailed understanding of the conformational landscape is crucial for rational drug design. Nuclear magnetic resonance (NMR) is the only method for structure determination in solution. However, it remains challenging to determine the structures of peptides using NMR because of very weak nuclear Overhauser effects (NOEs), the semiquantitative nature of the rotating frame Overhauser effect (ROE), and the low number of NOEs/ROEs in N-methylated peptides. In this study, we introduce a new approach to investigating the structures of modified macrocyclic peptides. We utilize exact NOEs (eNOEs) in viscous solvent mixtures to replicate various cellular environments. eNOEs provide detailed structural information for highly dynamic modified peptides. Structures of high precision were obtained for cyclosporin A, with a backbone atom rmsd of 0.10 Å. Distinct conformational states in different environments were identified for omphalotin A (OmphA), a fungal nematotoxic and multiple backbone N-methylated macrocyclic peptides. A model for cell-permeation is presented for OmphA, based on its structures in polar, apolar, and mixed polarity solvents. During the transition from a polar to an apolar environment, OmphA undergoes a rearrangement of its H-bonding network, accompanied by a cis to trans isomerization of the ω torsion angle within a type VIa β-turn. We hypothesize that the kinetics of these conformational transitions play a crucial role in determining the membrane-permeation capabilities of OmphA.

DOI: https://doi.org/10.1021/jacs.3c09367
J Am Chem Soc. 2023 Dec 13.

De Novo Discovery of Cysteine Frameworks for Developing Multicyclic Peptide Libraries for Ligand Discovery.

Jinjing Li, Hongtan Liu, Shuling Xiao, Shihui Fan, Xueting Cheng, Chuanliu Wu.

Conserved cysteine frameworks are essential components of disulfide-rich peptides (DRPs), which dominantly define the structural diversity of both naturally occurring and de novo-designed DRPs. However, there are only very limited numbers of conserved cysteine frameworks, and general methods enabling de novo discovery of cysteine frameworks with robust foldability are still not available. Here, we devised a "touchstone"-based strategy that relies on chasing oxidative foldability between two individual disulfide-rich folds on the phage surface to discover new cysteine frameworks from random sequences. Unique cysteine frameworks with a high degree of compatibility with phage display systems and broad sequence tolerance were successfully identified, which were subsequently exploited for the development of multicyclic DRP libraries, enabling the rapid discovery of new peptide ligands with low-nanomolar and picomolar binding affinity. This study provides an unprecedented method for exploring and exploiting the sequence and structure space of DRPs that is not readily accessible by existing strategies, holding the potential to revolutionize the study of DRPs and significantly advance the design and discovery of multicyclic peptide ligands and drugs.

DOI: https://doi.org/10.1021/jacs.3c11856
ACS Infect Dis. 2023 Dec 08. 9(12): 2593-2606

Antimicrobial Peptide-Peptoid Hybrids with and without Membrane Disruption.

Etienne Bonvin, Hippolyte Personne, Thierry Paschoud, Jérémie Reusser, Bee-Ha Gan, Alexandre Luscher, Thilo Köhler, Christian van Delden, Jean-Louis Reymond.

  Among synthetic analogues of antimicrobial peptides (AMPs) under investigation to address antimicrobial resistance, peptoids (N-alkylated oligoglycines) have been reported to act both by membrane disruption and on intracellular targets. Here we gradually introduced peptoid units into the membrane-disruptive undecapeptide KKLLKLLKLLL to test a possible transition toward intracellular targeting. We found that selected hybrids containing up to five peptoid units retained the parent AMP's α-helical folding, membrane disruption, and antimicrobial effects against Gram-negative bacteria including multidrug-resistant (MDR) strains of Pseudomonas aeruginosa and Klebsiella pneumoniae while showing reduced hemolysis and cell toxicities. Furthermore, some hybrids containing as few as three peptoid units as well as the full peptoid lost folding, membrane disruption, hemolysis, and cytotoxicity but displayed strong antibacterial activity under dilute medium conditions typical for proline-rich antimicrobial peptides (PrAMPs), pointing to intracellular targeting. These findings parallel previous reports that partially helical amphiphilic peptoids are privileged oligomers for antibiotic development.

Keywords:  Antimicrobial peptides; membrane disruption; peptoids; secondary structure

DOI:  https://doi.org/10.1021/acsinfecdis.3c00421
Eur Heart J. 2023 Dec 14. pii: ehad793. [Epub ahead of print]

Acid-sensing ion channel 1a blockade reduces myocardial injury in rodent models of myocardial infarction.

Meredith A Redd, Yusuke Yoshikawa, Nemat Khan, Maleeha Waqar, Natalie J Saez, Jennifer E Outhwaite, Jake S Russell, Amy D Hanna, Han S Chiu, Sing Yan Er, Neville J Butcher, Karine Mardon, John F Fraser, Mark L Smythe, Lachlan D Rash, Walter G Thomas, Glenn F King, Melissa E Reichelt, Nathan J Palpant.



Keywords:  Cardioprotection; Hi1a; Ischemia-reperfusion injury

DOI:  https://doi.org/10.1093/eurheartj/ehad793