Cell-Penetrating Peptides: Design, Synthesis, and Applications

Copolovici, Dana; Langel, Kent; Eriste, Elo; Langel, Ülo

doi:10.1021/nn4057269

Cited by 812 publications

(707 citation statements)

References 238 publications

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“…These results are important because this article documents the cell-penetrating capabilities for a member of peptaibol class of fungal metabolites (59,60). Cellpenetrating peptides (CPPs) (61)(62)(63) are an important class of drug transporters that can deliver large-cargo molecules through cell membranes and thus may be useful in clinical applications. The unique structural features of gichigamins, which include the absence of positively charged amino acid residues (e.g., Arg and Lys) in contrast with common CPPs, provide a template for the design of cell-penetrating molecules that can carry a payload across the outer cell membranes of mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mass-spectrometry-based metabolomics and molecular phylogeny data were used to identify a metabolically prolific strain of Tolypocladium that was obtained from a deep-water Great Lakes sediment sample. An investigation of the isolate's secondary metabolome resulted in the purification of a 22-mer peptaibol, gichigamin A (1). This peptidic natural product exhibited an amino acid sequence including several β-alanines that occurred in a repeating ααβ motif, causing the compound to adopt a unique right-handed 3 11 helical structure. The unusual secondary structure of 1 was confirmed by spectroscopic approaches including solution NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. Artificial and cell-based membrane permeability assays provided evidence that the unusual combination of structural features in gichigamins conferred on them an ability to penetrate the outer membranes of mammalian cells. Compound 1 exhibited potent in vitro cytotoxicity (GI 50 0.55 ± 0.04 μM) and in vivo antitumor effects in a MIA PaCa-2 xenograft mouse model. While the primary mechanism of cytotoxicity for 1 was consistent with ion leakage, we found that it was also able to directly depolarize mitochondria. Semisynthetic modification of 1 provided several analogs, including a C-terminus-linked coumarin derivative (22) that exhibited appreciably increased potency (GI 50 5.4 ± 0.1 nM), but lacked ion leakage capabilities associated with a majority of naturally occurring peptaibols such as alamethicin. Compound 22 was found to enter intact cells and induced cell death in a process that was preceded by mitochondrial depolarization.peptaibol | fungi | natural products | gichigamin | mitochondria N atural product chemical research has evolved in many extraordinary ways over the last decade largely due to the integration of powerful and accessible analytical chemistry (1, 2) and molecular biology (3, 4) tools. Some of these techniques have been applied toward the creation of natural product big-data sets in which genomic, metagenomic, metabolomic, and proteomic approaches are combined to obtain new insights into nature's remarkable chemical bounty (4-8). The predictive capabilities of these methods have helped guide efforts in several fertile areas of natural products research including the DNA cross-linking enediynes (9), bioactive cyanobacterial metabolites (10, 11), cytotoxic pentangular polyphenols (12), and thiopeptide antibiotics (13).The integration of analytical and molecular approaches is an effective way to find new natural product analogs that exhibit enhanced biological activities and improved pharmacological attributes (e.g., greater potency, better solubility, enhanced therapeutic index, etc.), but it also has the potential to uncover compounds with activities that are markedly dissimilar to other members of the queried chemical class. Nature is well known for its chemical repurposing capabilities, which allow populations of organisms to evolve new biological functions from existing molecular sc...

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Section: Discussionmentioning

confidence: 99%

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The most prominent example is the trans-activating transcriptional activator (TAT)-dervided peptide from human immunodeficiency virus 1 (HIV-1) which was shown to promote delivery of nucleic acids (211). Other examples are penetratin (drosophila), transportan and Pep-1 (HIV) (212,213). However, immune recognition and related toxicity problems limited a significant therapeutic success since many of these compounds are not well tolerated in vivo.…”

Section: Potential Relevance and Current Bottlenecks Of Mir-directed mentioning

confidence: 99%

“…Considering the mode of action of cell penetrating peptides (CPP), many theories were discussed (e.g. proton sponge theory) (212,216). Langel et al and others put much effort in defining rules and characteristics of CPP and designed artificial hybrids that carry advantageous features for intracellular cargo delivery.…”

Section: Potential Relevance and Current Bottlenecks Of Mir-directed mentioning

confidence: 99%

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

Weidle

Dickopf

Hintermair

et al. 2018

CGP

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“…10 CPPs are peptides of residues that have the ability to cross the cell membrane and enter into most cell types. 11,12 The best described is the trans-activating transcriptional activator from the human immunodeficiency virus 1 (HIV-TAT), 13,14 but CPPs of different origins are now known. 15,16 The secondary structure of CPPs is an important feature for their cellular uptake, 17 with helical structure being associated with strong CPP-membrane interactions.…”

Section: Introductionmentioning

confidence: 99%

Enhancing Antitumor Immune Responses by Optimized Combinations of Cell-penetrating Peptide-based Vaccines and Adjuvants

Belnoue¹,

Berardino-Besson

Gaertner

et al. 2016

Molecular Therapy

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Cell penetrating peptides (CPPs) from the protein ZEBRA are promising candidates to exploit in therapeutic cancer vaccines, since they can transport antigenic cargos into dendritic cells and induce tumor-specific T cells. Employing CPPs for a given cancer indication will require engineering to include relevant tumor-associated epitopes, administration with an appropriate adjuvant, and testing for antitumor immunity. We assessed the importance of structural characteristics, efficiency of in vitro transduction of target cells, and choice of adjuvant in inducing the two key elements in antitumor immunity, CD4 and CD8 T cells, as well as control of tumor growth in vivo. Structural characteristics associated with CPP function varied according to CPP truncations and cargo epitope composition, and correlated with in vitro transduction efficiency. However, subsequent in vivo capacity to induce CD4 and CD8 T cells was not always predicted by in vitro results. We determined that the critical parameter for in vivo efficacy using aggressive mouse tumor models was the choice of adjuvant. Optimal pairing of a particular ZEBRA-CPP sequence and antigenic cargo together with adjuvant induced potent antitumor immunity. Our results highlight the irreplaceable role of in vivo testing of novel vaccine constructs together with adjuvants to select combinations for further development.

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Cell-Penetrating Peptides: Design, Synthesis, and Applications

Cited by 812 publications

References 238 publications

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

Enhancing Antitumor Immune Responses by Optimized Combinations of Cell-penetrating Peptide-based Vaccines and Adjuvants

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