bims-cepepe 2024-10-20 papers

bims-cepepe

Biomed News

on Cell-penetrating peptides

Issue of 2024–10–20
eleven papers selected by
Henry Lamb, Queensland University of Technology

Peptides as innovative strategies to combat drug resistance in cancer therapy.
P-Sulfonatocalix[4]arene turns peptide aggregates into an efficient cell-penetrating peptide.
Short Peptides as Powerful Arsenal for Smart Fighting Cancer.
Involvement of Proton-Coupled Organic Cation Antiporter in Human Blood-Brain Barrier Transport of Mesoridazine and Metoclopramide.
De novo designed YK peptides forming reversible amyloid for synthetic protein condensates in mammalian cells.
BBBper: A Machine Learning-based Online Tool for Blood-Brain Barrier (BBB) Permeability Prediction.
Advancements in therapeutic peptides: Shaping the future of cancer treatment.
De novo Design of Tryptophan containing Broad-Spectrum Cationic Antimicrobial Octapeptides.
AlphaFold Ensemble Competition Screens Enable Peptide Binder Design with Single-Residue Sensitivity.
Surgery enhances the effectiveness of peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumors.
Branched oncolytic peptides target HSPGs, inhibit metastasis, and trigger the release of molecular determinants of immunogenic cell death in pancreatic cancer.

Drug Discov Today. 2024 Oct 10. pii: S1359-6446(24)00331-3. [Epub ahead of print] 104206

Peptides as innovative strategies to combat drug resistance in cancer therapy.

Henry O Lamb, Aurélie H Benfield, Sónia Troeira Henriques.

  Drug resistance is the leading cause of treatment failure in patients with cancer. Thus, innovative therapeutic strategies are required to overcome this critical challenge and improve patient outcomes. In this review, we examine the potential of peptide-based therapies to combat drug resistance in cancer. We highlight the unique strategies and mechanisms that can be explored by using peptides, including their ability to selectively target tumours, facilitate drug delivery into cancer cells, and inhibit key intracellular proteins that drive cancer progression and resistance. Peptides offer a promising approach to overcoming both intrinsic and adaptative cancer resistance against chemotherapy, targeted therapies, and biologics.

Keywords:  anticancer therapies; cyclic peptides; drug resistance; membrane-active peptides; peptide–drug conjugate; protein–protein interactions

DOI:  https://doi.org/10.1016/j.drudis.2024.104206
RSC Adv. 2024 Oct 09. 14(44): 32460-32470

P-Sulfonatocalix[4]arene turns peptide aggregates into an efficient cell-penetrating peptide.

Mahsima Heydari, Najmeh Salehi, Reza Zadmard, Werner M Nau, Khosro Khajeh, Zahra Azizi, Amir Norouzy.

A novel cell-penetrating peptide (CPP) called FAM-Y4R4, with FAM as a fluorescent probe, was developed. Initially, we aimed to use Y4 as a supramolecular host for water-insoluble drugs, with R4 driving the complex into cells. However, an unexpected hurdle was discovered; the peptide self-assembled into amorphous aggregates, rendering it ineffective for our intended purpose. Molecular dynamics simulations revealed that intermolecular cation-π interactions between arginine and tyrosine caused this aggregation. By decorating the R4 sidechains with p-sulfonatocalix[4]arene (CX4), we successfully dissolved most of the aggregates, significantly improved the peptide's solubility and enhanced the cell uptake with MCF7 and A549 cells via both direct penetration and endocytosis. The binding strength between CX4 and R4, as well as the interaction between curcumin and tyrosines was quantified. Encouragingly, our results showed that FAM-Y4R4, with CX4, effectively delivered curcumin - as a model for poorly water-soluble drugs - into cells which exhibited potent anticancer activity. Using R4/CX4 instead of the conventional R7-9 oligoarginine-based CPP simplifies peptide synthesis and offers higher yields. CX4 shows promise for addressing aggregation issues in other peptides that undergo a similar aggregation mechanism.

DOI: https://doi.org/10.1039/d4ra06124a
Cancers (Basel). 2024 Sep 24. pii: 3254. [Epub ahead of print]16(19):

Short Peptides as Powerful Arsenal for Smart Fighting Cancer.

Joanna Bojarska, Wojciech M Wolf.

  Short peptides have been coming around as a strong weapon in the fight against cancer on all fronts-in immuno-, chemo-, and radiotherapy, and also in combinatorial approaches. Moreover, short peptides have relevance in cancer imaging or 3D culture. Thanks to the natural 'smart' nature of short peptides, their unique structural features, as well as recent progress in biotechnological and bioinformatics development, short peptides are playing an enormous role in evolving cutting-edge strategies. Self-assembling short peptides may create excellent structures to stimulate cytotoxic immune responses, which is essential for cancer immunotherapy. Short peptides can help establish versatile strategies with high biosafety and effectiveness. Supramolecular short peptide-based cancer vaccines entered clinical trials. Peptide assemblies can be platforms for the delivery of antigens, adjuvants, immune cells, and/or drugs. Short peptides have been unappreciated, especially in the vaccine aspect. Meanwhile, they still hide the undiscovered unlimited potential. Here, we provide a timely update on this highly active and fast-evolving field.

Keywords:  adjuvant; antigen; cancer; diagnosis; immunotherapeutic drugs; self-assembled peptides; short peptides; therapy; vaccine; vaccine delivery

DOI:  https://doi.org/10.3390/cancers16193254
Biol Pharm Bull. 2024 ;47(10): 1662-1667

Involvement of Proton-Coupled Organic Cation Antiporter in Human Blood-Brain Barrier Transport of Mesoridazine and Metoclopramide.

Yasuyuki Debori, Tomoko Igari, Masanori Nakakariya, Hideki Hirabayashi, Kazunobu Aoyama, Nobuyuki Amano, Toshiki Kurosawa, Yoshiyuki Kubo, Yoshiharu Deguchi.

  Mesoridazine and metoclopramide are cationic drugs that are distributed in the human brain despite being substrates of multidrug resistance protein 1 (MDR1), an efflux transporter expressed at the blood-brain barrier (BBB). We investigated their transport mechanisms at the BBB using hCMEC/D3, a human cerebral microvascular endothelial cell line often used as an in vitro BBB model. The cells exhibited time- and concentration-dependent uptake of mesoridazine and metoclopramide, with Km values of 34 and 277 µM, respectively. The uptake of both drugs significantly decreased in the presence of typical inhibitors and/or substrates of the H+-coupled organic cation (H+/OC) antiporter but not in the presence of inhibitors or substrates of organic cation transporters (OCTs), OCTN2, OATPs, SLC35F2, or the plasma membrane monoamine transporter (PMAT). Furthermore, metoclopramide uptake by hCMEC/D3 cells was pH- and energy-dependent, whereas mesoridazine uptake was unaffected by intracellular acidification and treatment with metabolic inhibitors. These results suggest that the H+/OC antiporter is involved in the influx of mesoridazine and metoclopramide into the brain across the BBB.

Keywords:  blood–brain barrier; cationic drug; hCMEC/D3 cell; membrane transport; transporter

DOI:  https://doi.org/10.1248/bpb.b24-00329
Nat Commun. 2024 Oct 18. 15(1): 8503

De novo designed YK peptides forming reversible amyloid for synthetic protein condensates in mammalian cells.

Takayuki Miki, Masahiro Hashimoto, Hiroki Takahashi, Masatoshi Shimizu, Sae Nakayama, Tadaomi Furuta, Hisakazu Mihara.

In mammalian cells, protein condensates underlie diverse cell functions. Intensive synthetic biological research has been devoted to fabricating liquid droplets using de novo peptides/proteins designed from scratch in test tubes or bacterial cells. However, the development of de novo sequences for synthetic droplets forming in eukaryotes is challenging. Here, we report YK peptides, comprising 9-15 residues of alternating repeats of tyrosine and lysine, which form reversible amyloid-like fibrils accompanied by binding with poly-anion species such as ATP. By genetically tagging the YK peptide, superfolder GFPs assemble into artificial liquid-like droplets in living cells. Rational design of the YK system allows fine-tuning of the fluidity and construction of multi-component droplets. The YK system not only facilitates intracellular reconstitution of simplified models for natural protein condensates, but it also provides a toolbox for the systematic creation of droplets with different dynamics and composition for in situ evaluation.

DOI: https://doi.org/10.1038/s41467-024-52708-5
CNS Neurol Disord Drug Targets. 2024 Oct 16.

BBBper: A Machine Learning-based Online Tool for Blood-Brain Barrier (BBB) Permeability Prediction.

Pawan Kumar, Vandana Saini, Dinesh Gupta, Pooja A Chawla, Ajit Kumar.

   AIMS: Neuronal disorders have affected more than 15% of the world's population, signifying the importance of continued design and development of drugs that can cross the Blood-Brain Barrier (BBB).
BACKGROUND: BBB limits the permeability of external compounds by 98% to maintain and regulate brain homeostasis. Hence, BBB permeability prediction is vital to predict the activity of a drug-like substance.
OBJECTIVE: Here, we report about developing BBBper (Blood-Brain Barrier permeability prediction) using machine learning tool.
METHOD: A supervised machine learning-based online tool, based on physicochemical parameters to predict the BBB permeability of given chemical compounds was developed. The user-end webpage was developed in HTML and linked with back-end server by a python script to run user queries and results.
RESULT: BBBper uses a random forest algorithm at the back end, showing 97% accuracy on the external dataset, compared to 70-92% accuracy of currently available web-based BBB permeability prediction tools.
CONCLUSION: The BBBper web tool is freely available at http://bbbper.mdu.ac.in.

Keywords:  BBB permeability.; Blood-brain permeation; Python; Web-server tool; random forest; supervised machine learning

DOI:  https://doi.org/10.2174/0118715273328174241007060331
Biochim Biophys Acta Rev Cancer. 2024 Oct 14. pii: S0304-419X(24)00128-8. [Epub ahead of print] 189197

Advancements in therapeutic peptides: Shaping the future of cancer treatment.

Xiaojie Chen, Zhiwei Zhao, Kyle Vaughn Laster, Kangdong Liu, Zigang Dong.

  In the evolving landscape of cancer treatment, therapeutic peptides are assuming to play an increasingly vital role. Although the number of peptide drugs available for clinical cancer treatment is currently limited, extensive preclinical research is underway, presenting a promising trajectory for the future. The collaborative efforts of natural anti-cancer peptides (ACPs) and synthetic ACPs, propelled by advancements in molecular biology and peptide chemistry, are steering remarkable progress in this domain. We explores the intricate mechanisms underlying the anti-cancer effects of these peptides. The exploration of innovative strategies, including cancer immunotherapy and advanced drug delivery systems, is likely to contribute to the increasing presenceuse of peptide drugs in clinical cancer care. Furthermore, we delve into the potential implications and challenges associated with this anticipated shift, empHasizing the need for continued research and development to unlock the full therapeutic potential of peptide drugs in cancer treatment.

Keywords:  Anti-cancer peptides; Clinical therapeutics; Drug delivery systems; Immunotherapy; Mechanism

DOI:  https://doi.org/10.1016/j.bbcan.2024.189197
ChemMedChem. 2024 Oct 14. e202400566

De novo Design of Tryptophan containing Broad-Spectrum Cationic Antimicrobial Octapeptides.

Sunanda Chatterjee, Tanumoy Sarkar, Vignesh S R, Pradeep Kumar Sundaravadivelu, Rajkumar Purushottambhai Thummar, Priyadarshi Satpati.

  With the advent of antibiotic resistant organisms, development of alternate classes of molecules other than antibiotics to combat microbial infections, have become extremely important. In this context, antimicrobial peptides have taken center stage of antimicrobial therapeutic research. In this work, we have reported two cationic antimicrobial octapeptides WRL and LWRF, with broad spectrum antimicrobial activities against several strains of ESKAPE pathogens. Both the peptides were membrane associative and induced microbial cell death through membranolysis, being selective towards microbial membranes over mammalian membranes. The AMPs were unstructured in water, adopting partial helical conformation in the presence of microbial membrane mimics. Electrostatic interaction formed the primary basis of peptide-membrane interactions. WRL was more potent, salt tolerant and faster acting of the two AMPs, owing to the presence of two tryptophan residues against that of one in LWRF. Increased tryptophan number in WRL enhanced its membrane association ability, resulting in higher antimicrobial potency but lower selectivity. This experimental and computational work, established that an optimum number of tryptophan residues and their position is critical for obtaining high antimicrobial potency and selectivity simultaneously in cationic AMPs. Understanding the peptide membrane interactions in atomistic details can lead to development of better antimicrobial therapeutics in future.

Keywords:  Antimicrobial peptides, Peptide-membrane interaction, membrane selectivity, Tryptophan rich AMPs, Membranolytic peptides

DOI:  https://doi.org/10.1002/cmdc.202400566
ACS Chem Biol. 2024 Oct 18. 19(10): 2198-2205

AlphaFold Ensemble Competition Screens Enable Peptide Binder Design with Single-Residue Sensitivity.

Pernille Vosbein, Paula Paredes Vergara, Danny T Huang, Andrew R Thomson.

Understanding the relationship between the sequence and binding energy in peptide-protein interactions is an important challenge in chemical biology. A prominent example is ubiquitin interacting motifs (UIMs), which are short peptide sequences that recognize ubiquitin and which bind individual ubiquitin proteins with a weak affinity. Though the sequence characteristics of UIMs are well understood, the relationship between the sequence and ubiquitin binding affinity has not yet been fully characterized. Herein, we study the first UIM of Vps27 as a model system. Using an experimental alanine scan, we were able to rank the relative contribution of each hydrophobic residue of this UIM to ubiquitin binding. These results were correlated with AlphaFold displacement studies, in which AlphaFold is used to predict the stronger binder by presenting a target protein with two potential peptide ligands. We demonstrate that by generating large numbers of models and using the consensus bound-state AlphaFold competition experiments can be sensitive to single-residue variations. We furthermore show that to fully recapitulate the binding trends observed for ubiquitin, it is necessary to screen AlphaFold models that incorporate a "decoy" binding site to prevent the displaced peptide from interfering with the actual binding site. Overall, it is shown that AlphaFold can be used as a powerful tool for peptide binder design and that when large ensembles of models are used, AlphaFold predictions can be sensitive to very small energetic changes arising from single-residue alterations to a binder.

DOI: https://doi.org/10.1021/acschembio.4c00418
Surgery. 2024 Oct 11. pii: S0039-6060(24)00705-0. [Epub ahead of print]

Surgery enhances the effectiveness of peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumors.

Joseph Tobias, Sara Abou Azar, Rushabh Gujarathi, Rachel Nordgren, Tanaz Vaghaiwalla, J Michael Millis, Nicholas Feinberg, Chih-Yi Liao, Xavier M Keutgen.

BACKGROUND: With the advent of peptide receptor radionuclide therapy, the timing and sequence of surgery in the treatment of metastatic gastroenteropancreatic neuroendocrine tumors merits further study. We hypothesized that surgery before peptide receptor radionuclide therapy might enhance its effectiveness in patients with metastatic gastroenteropancreatic neuroendocrine tumors.
METHODS: Eighty-nine patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors treated with 177Lutetium-dotatate peptide receptor radionuclide therapy between 2018 and 2023 were included. Fifty-six patients underwent surgery (primary tumor resection and/or liver debulking) before peptide receptor radionuclide therapy and 33 patients did not. Primary outcome was progression-free survival according to Response Evaluation Criteria in Solid Tumors. Pretreatment dotatate positron emission tomography/computed tomography was used to calculate tumor volumes.
RESULTS: The surgery and no-surgery groups were well-matched. Median progression-free survival after peptide receptor radionuclide therapy was 15.6 months (interquartile range, 9.1-22.7 months) in the no-surgery group compared with 26.1 months (interquartile range, 12.7-38.1 months) in the surgery group (P = .04). On subgroup analysis, median progression-free survival was 18.1 months (interquartile range, 11.9-38.4 months) in patients who underwent primary tumor resection only compared with 26.2 months (interquartile range, 14.0-38.1 months) in patients who underwent liver debulking (P = .04). Tumor volume was lowest in patients who underwent liver debulking (median 146.07 mL3) compared with no surgery (median 626.42 mL3) (P = .001). On univariable analysis, a tumor volume <138.8 mL3 was associated with longer progression-free survival (hazard ratio, 2.03; 95% confidence interval, 0.95-4.34, P = .05), with a median progression-free survival of 38.1 months (interquartile range, 16.9-41.3 months) compared with 17.8 months (interquartile range, 10.8-28.7 months).
CONCLUSION: Surgery may enhance the effectiveness of 177Lutetium-dotatate in the treatment of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors. This positive effect may be the result of a lower tumor volume in patients after surgery. Our findings fortify the concept of using surgical debulking to improve systemic therapies such as peptide receptor radionuclide therapy.

DOI: https://doi.org/10.1016/j.surg.2024.06.065
Front Mol Biosci. 2024 ;11 1429163

Branched oncolytic peptides target HSPGs, inhibit metastasis, and trigger the release of molecular determinants of immunogenic cell death in pancreatic cancer.

Alessandro Rencinai, Eva Tollapi, Giulia Marianantoni, Jlenia Brunetti, Tania Henriquez, Alessandro Pini, Luisa Bracci, Chiara Falciani.

  Immunogenic cell death (ICD) can be exploited to treat non-immunoreactive tumors that do not respond to current standard and innovative therapies. Not all chemotherapeutics trigger ICD, among those that do exert this effect, there are anthracyclines, irinotecan, some platinum derivatives and oncolytic peptides. We studied two new branched oncolytic peptides, BOP7 and BOP9 that proved to elicit the release of damage-associated molecular patterns DAMPS, mediators of ICD, in pancreatic cancer cells. The two BOPs selectively bound and killed tumor cells, particularly PANC-1 and Mia PaCa-2, but not cells of non-tumor origin such as RAW 264.7, CHO-K1 and pgsA-745. The cancer selectivity of the two BOPs may be attributed to their repeated cationic sequences, which enable multivalent binding to heparan sulfate glycosaminoglycans (HSPGs), bearing multiple anionic sulfation patterns on cancer cells. This interaction of BOPs with HSPGs not only fosters an anti-metastatic effect in vitro, as demonstrated by reduced adhesion and migration of PANC-1 cancer cells, but also shows promising tumor-specific cytotoxicity and low hemolytic activity. Remarkably, the cytotoxicity induced by BOPs triggers the release of DAMPs, particularly HMGB1, IFN-β and ATP, by dying cells, persisting longer than the cytotoxicity of conventional chemotherapeutic agents such as irinotecan and daunorubicin. An in vivo assay in nude mice showed an encouraging 20% inhibition of tumor grafting and growth in a pancreatic cancer model by BOP9.

Keywords:  danger associated molecular patterns; immunogenic cell death; metastasis; oncolytic peptides; pancreatic cancer

DOI:  https://doi.org/10.3389/fmolb.2024.1429163