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1. Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption

   https://doi.org/10.1038/s41598-021-91670-w  

   Comert, Fatih ; Heinrich, Frank ; Chowdhury, Ananda ; Schoeneck, Mason ; Darling, Caitlin ; Anderson, Kyle W. ; Libardo, M. Daben ; Angeles-Boza, Alfredo M. ; Silin, Vitalii ; Cotten, Myriam L. ; et al ( December 2021 , Scientific Reports)

   null (Ed.)

   Abstract In the search for novel broad-spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest. Characterizing their biologically-active conformations and minimum motifs for function represents a requisite step to developing them into efficacious and safe therapeutics. Here, we demonstrate that metallating HDPs with Cu 2+ is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that prepared as Cu 2+ -complexes, the peptides not only physically but also chemically damage lipid membranes. Our testing ground features piscidins 1 and 3 (P1/3), two amphipathic, histidine-rich, membrane-interacting, and cell-penetrating HDPs that are α-helical bound to membranes. To investigate their membrane location, permeabilization effects, and lipid-oxidation capability, we employ neutron reflectometry, impedance spectroscopy, neutron diffraction, and UV spectroscopy. While P1-apo is more potent than P3-apo, metallation boosts their cytotoxicities by up to two- and seven-fold, respectively. Remarkably, P3-Cu 2+ is particularly effective at inserting in bilayers, causing water crevices in the hydrocarbon region and placing Cu 2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where complexing HDPs with Cu 2+ to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics. 

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2. Down‐regulating Proteolysis to Enhance Anticancer Activity of Peptide Nanofibers

   https://doi.org/10.1002/asia.201800875  

   Li, Jie ; Du, Xuewen ; Powell, Devon J. ; Zhou, Rong ; Shi, Junfeng ; He, Hongjian ; Feng, Zhaoqianqi ; Xu, Bing ( July 2018 , Chemistry – An Asian Journal)

   Nanofibers of short peptides are emerging as a promising type of agents for inhibiting cancer cells. But the proteolysis of peptides decreases the anticancer efficacy of the peptide nanofibers. Here we show that decreasing the activity of proteasomes enhance the activity of peptide nanofibers for inhibiting cancer cells. Based on the structure of galactin‐3, we designed a heptapeptide, which self‐assembles to form nanofibers. The nanofibers of the heptapeptide exhibit moderate cytotoxicity to three representative cancer cell lines (HeLa, MCF‐7, and HepG2), largely due to the proteolysis of the peptides. Using a clinically approved proteasome inhibitor, bortezomib, to treat the cancer cells significantly decreases the proteolysis of the peptides and enhances the activity of the peptide nanofibers for inhibiting the cancer cells. This work illustrates a promising approach for enhancing the anticancer efficacy of peptide nanofibers by modulating intracellular protein degradation machinery, as well as provides insights for understanding the cytotoxicity of aberrant protein or peptide aggregates in complicated cellular environment.

    

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3. Instructed‐assembly of small peptides inhibits drug‐resistant prostate cancer cells

   https://doi.org/10.1002/pep2.24123  

   Feng, Zhaoqianqi ; Wang, Huaimin ; Yi, Meihui ; Lo, Chieh‐Yun ; Sallee, Ashanti ; Hsieh, Jer‐Tsong ; Xu, Bing ( June 2019 , Peptide Science)

   Despite multiple new‐drug approvals in recent years, prostate cancer remains a global health challenge because of the prostate cancers are resistant to androgen deprivation therapy. Here, we show that a small D‐phosphopeptide undergoes prostatic acid phosphatase (PAP)‐instructed self‐assembly for inhibiting castration‐resistant prostate cancer (CRPC) cells. Specifically, the installation of phosphate at the C‐terminal of a D‐tripeptide results in the D‐phosphopeptide. Dephosphorylating the D‐phosphopeptide by PAP forms uniform nanofibers that inhibit VCaP, a CRPC cell. A non‐hydrolyzable phosphate analogue of the D‐phosphopeptide, which shares similar self‐assembling properties with the D‐phosphopeptide, confirms that PAP‐instructed assembly is critical for the inhibition of VCaP. This work, for the first time, demonstrates PAP‐instructed self‐assembly of peptides for selective inhibiting CRPC cells.

    

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4. Regulating the Rate of Molecular Self‐Assembly for Targeting Cancer Cells

   https://doi.org/10.1002/ange.201600753  

   Zhou, Jie ; Du, Xuewen ; Xu, Bing ( April 2016 , Angewandte Chemie)

   Besides tight and specific ligand–receptor interactions, the rate regulation of the formation of molecular assemblies is one of fundamental features of cells. But the latter receives little exploration for developing anticancer therapeutics. Here we show that a simple molecular design of the substrates of phosphatases—tailoring the number of phosphates on peptidic substrates—is able to regulate the rate of molecular self‐assembly of the enzyme reaction product. Such a rate regulation allows selective inhibition of osteosarcoma cells over hepatocytes, which promises to target cancer cells in a specific organ. Moreover, our result reveals that the direct measurement of the rate of the self‐assembly in a cell‐based assay provides precise assessment of the cell targeting capability of self‐assembly. This work, as the first report establishing rate regulation of a multiple‐step process to inhibit cells selectively, illustrates a fundamentally new approach for controlling the fate of cells.

    

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5. In Silico Design of Optimal Dissolution Kinetics of Fe‐Doped ZnO Nanoparticles Results in Cancer‐Specific Toxicity in a Preclinical Rodent Model

   https://doi.org/10.1002/adhm.201601379  

   Manshian, Bella B. ; Pokhrel, Suman ; Himmelreich, Uwe ; Tämm, Kaido ; Sikk, Lauri ; Fernández, Alberto ; Rallo, Robert ; Tamm, Tarmo ; Mädler, Lutz ; Soenen, Stefaan J. ( February 2017 , Advanced Healthcare Materials)

   Cancer cells have unique but widely varying characteristics that have proven them difficult to be treated by classical therapeutics and calls for novel and selective treatment options. Nanomaterials (NMs) have been shown to display biological effects as a function of their chemical composition, and the extent and exact nature of these effects can vary between different biological environments. Here, ZnO NMs are doped with increasing levels of Fe, which allows to finely tune their dissolution rate resulting in significant differences in their biological behavior on cancer or normal cells. Based on in silico analysis, 2% Fe‐doped ZnO NMs are found to be optimal to cause selective cancer cell death, which is confirmed in both cultured cells and syngeneic tumor models, where they also reduce metastasis formation. These results show that upon tuning NM chemical composition, NMs can be designed as a targeted selective anticancer therapy.

    

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