Design of human lactoferricin derived antitumor peptides-activity and specificity against malignant melanoma in 2D and 3D model studies

Grissenberger, Sarah; Riedl, Sabrina; Rinner, Beate; Leber, Regina; Zweytick, Dagmar

doi:10.1016/j.bbamem.2020.183264

Cited by 8 publications

(27 citation statements)

References 39 publications

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“…Furthermore, the 10 amino acids at the N-terminal end of cecropin can be used and repeated three times to create the CB1 peptide [ 85 ]. Grissenberger et al (2020) obtained anticancer peptide fractions from lactoferrin residues 21 to31, including retro dipeptides DIM-LF11-322 and R-DIM-PLF11-215 characterized by a net charge of +9 and a potent activity and selectivity against cancer cells [ 94 ].…”

Section: Sequence Template Methods Of Rational Design Of Anticancementioning

confidence: 99%

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

2020

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Peptides are naturally produced by all organisms and exhibit a wide range of physiological, immunomodulatory, and wound healing functions. Furthermore, they can provide with protection against microorganisms and tumor cells. Their multifaceted performance, high selectivity, and reduced toxicity have positioned them as effective therapeutic agents, representing a positive economic impact for pharmaceutical companies. Currently, efforts have been made to invest in the development of new peptides with antimicrobial and anticancer properties, but the poor stability of these molecules in physiological environments has triggered a bottleneck. Therefore, some tools, such as nanotechnology and in silico approaches can be applied as alternatives to try to overcome these obstacles. In silico studies provide a priori knowledge that can lead to the development of new anticancer peptides with enhanced biological activity and improved stability. This review focuses on the current status of research in peptides with dual antimicrobial–anticancer activity, including advances in computational biology using in silico analyses as a powerful tool for the study and rational design of these types of peptides.

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Section: Sequence Template Methods Of Rational Design Of Anticancementioning

confidence: 99%

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

2020

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“…Cationic antitumor peptides derived from the human host defense peptide Lactoferricin [22] studied in our lab (PCT/EP2014/050330; US 14/760,445; EP 14700349.5) have been shown to selectively kill cancer cells of different types, including malignant melanoma and their metastases [23][24][25][26] and glioblastoma [24] in 2D and 3D [26] in vitro and in vivo [25] by targeting the negatively charged lipid phosphatidylserine (PS), specifically exposed by cell membranes of cancer cells [27,28]. Cell death appeared by peptide-induced apoptosis [24], a process normally blocked, e.g., in melanoma by inhibition of Apaf-1 [29].…”

Section: Introductionmentioning

confidence: 99%

“…Cell death appeared by peptide-induced apoptosis [24], a process normally blocked, e.g., in melanoma by inhibition of Apaf-1 [29]. Several highly active and specific peptide derivatives with about 5-to 25-fold specificity for melanoma over normal dermal fibroblasts or melanocytes were designed with a similar pattern of a secondary structure comprising a mostly proline induced loop in the middle of the peptide flanked by two helices or two β-strands and a net charge of +9 and above [24,26].…”

Section: Introductionmentioning

confidence: 99%

“…One of these peptides, R-DIM-P-LF11-322, exhibits selective activity against the cancer cell marker PS on model systems and cytotoxicity against melanoma, glioblastoma and rhabdomyosarcoma without significant effect on non-neoplastic cells as melanocytes or fibroblasts at antitumor-active concentrations [23,24,26]. Through the deletion of two Phe residues, hydrophobicity and slight cytotoxicity were decreased, resulting in a still nicely active peptide R-DIM-P-LF11-334 [25].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, further optimization regarding proteolytic stability was performed. In a recent study, Grissenberger et al reported about (retro) di-peptide R-DIM-P-LF11-215 (RDP215) with a net charge of +9 and moderate hydrophobicity that exhibited the highest specific antitumor activity of the peptide derivatives in 2D and 3D in vitro studies so far [26], which might potentially be due to an increase in stability.…”

Section: Introductionmentioning

confidence: 99%

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Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma

Maxian

Gerlitz

Riedl

et al. 2021

IJMS

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The study investigates the antitumor effect of two cationic peptides, R-DIM-P-LF11-215 (RDP215) and the D-amino acid variant 9D-R-DIM-P-LF11-215 (9D-RDP215), targeting the negatively charged lipid phosphatidylserine (PS) exposed by cancer cells, such as of melanoma and glioblastoma. Model studies mimicking cancer and non-cancer membranes revealed the specificity for the cancer-mimic PS by both peptides with a slightly stronger impact by the D-peptide. Accordingly, membrane effects studied by DSC, leakage and quenching experiments were solely induced by the peptides when the cancer mimic PS was present. Circular dichroism revealed a sole increase in β-sheet conformation in the presence of the cancer mimic for both peptides; only 9D-RDP215 showed increased structure already in the buffer. Ex vitro stability studies by SDS-PAGE as well as in vitro with melanoma A375 revealed a stabilizing effect of D-amino acids in the presence of serum, which was also confirmed in 2D and 3D in vitro experiments on glioblastoma LN-229. 9D-RDP215 was additionally able to pass a BBB model, whereupon it induced significant levels of cell death in LN-229 spheroids. Summarized, the study encourages the introduction of D-amino acids in the design of antitumor peptides for the improvement of their stable antitumor activity.

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Lectin‐anticancer peptide fusion demonstrates a significant cancer‐cell‐selective cytotoxic effect and inspires the production of “clickable” anticancer peptide in Escherichia coli

Pasupuleti,

Riedl,

Saltor Núñez

et al. 2023

Protein Science

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Targeted killing of tumor cells while protecting healthy cells is the pressing priority in cancer treatment. Lectins that target a specific glycan marker abundant on cancer cells can be valuable new tools for selective cancer cell killing. The lectin shiga‐like toxin 1 B subunit (Stx1B) is an example that specifically binds globotriaosylceramide (CD77 or Gb3), which is overexpressed in certain cancers. In this study, a human lactoferricin‐derived synthetic retro di‐peptide R‐DIM‐P‐LF11‐215 with antitumor efficacy was fused to the lectin Stx1B to selectively target and kill Gb3+ cancer cells. We produced lectin‐peptide fusion proteins in E. coli, isolated them by Gb3‐affinity chromatography and assessed their ability to selectively kill Gb3+ cancer cells in a Calcein AM assay. Furthermore, to expand the applications of R‐DIM‐P‐LF11‐215 in developing therapeutic bioconjugates, we labelled R‐DIM‐P‐LF11‐215 with the unique reactive non‐canonical amino acid Nε‐((2‐azidoethoxy)carbonyl)‐L‐lysine (AzK) at a selected position by amber stop codon suppression. The R‐DIM‐P‐LF11‐215 20AzK and the unlabeled R‐DIM‐P‐LF11‐215 parent peptide were produced as GST‐fusion proteins for soluble expression in E. coli for the first time. We purified both variants by size‐exclusion chromatography and analyzed their peptide masses. Finally, a cyanin 3 fluorophore was covalently conjugated to R‐DIM‐P‐LF11‐215 20AzK by strain‐promoted alkyne‐azide cycloaddition. Our results showed that the recombinant lectin‐peptide fusion R‐DIM‐P‐LF11‐215‐Stx1B killed >99% Gb3+ HeLa cells while Gb3‐negative cells were unaffected. The peptides R‐DIM‐P‐LF11‐215 and R‐DIM‐P‐LF11‐215 20AzK were produced recombinantly in E. coli in satisfactory amounts and were tested functional by cytotoxicity and cell‐binding assays, respectively.This article is protected by copyright. All rights reserved.

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Design of human lactoferricin derived antitumor peptides-activity and specificity against malignant melanoma in 2D and 3D model studies

Cited by 8 publications

References 39 publications

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma

Lectin‐anticancer peptide fusion demonstrates a significant cancer‐cell‐selective cytotoxic effect and inspires the production of “clickable” anticancer peptide in Escherichia coli

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