In silico design and optimization of selective membranolytic anticancer peptides

Gabernet, Gisela; Gautschi, Damian; Müller, Alex T.; Neuhaus, Claudia S.; Armbrecht, Lucas; Dittrich, Petra S.; Hiss, Jan A.; Schneider, Gisbert

doi:10.1038/s41598-019-47568-9

Cited by 55 publications

(51 citation statements)

References 44 publications

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“…Anticancer peptide creation should consider the peptide structure, mode of action, selectivity and efficacy to specific cancer cells ( 69 , 70 ). In the present review, active peptides were classified into three types depending on their actions, including: i) Molecularly targeted peptides, which directly act on cancer cells via cytotoxic, anti-proliferative and apoptotic activities; ii) 'guiding missile' peptides or binding peptides, which are drug binding peptides used for transporting drugs into the cancer cell targets; and iii) cell-stimulating peptides that indirectly effect other stimulating cells to kill cancer cells, such as via immunomodulatory activities and hormone receptors ( 71 - 73 ).…”

Section: Classification Of Acpsmentioning

confidence: 99%

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

2020

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Cancer is currently ineffectively treated using therapeutic drugs, and is also able to resist drug action, resulting in increased side effects following drug treatment. A novel therapeutic strategy against cancer cells is the use of anticancer peptides (ACPs). The physicochemical properties, amino acid composition and the addition of chemical groups on the ACP sequence influences their conformation, net charge and orientation of the secondary structure, leading to an effect on targeting specificity and ACP-cell interaction, as well as peptide penetrating capability, stability and efficacy. ACPs have been developed from both naturally occurring and modified peptides by substituting neutral or anionic amino acid residues with cationic amino acid residues, or by adding a chemical group. The modified peptides lead to an increase in the effectiveness of cancer therapy. Due to this effectiveness, ACPs have recently been improved to form drugs and vaccines, which have sequentially been evaluated in various phases of clinical trials. The development of the ACPs remains focused on generating newly modified ACPs for clinical application in order to decrease the incidence of new cancer cases and decrease the mortality rate. The present review could further facilitate the design of ACPs and increase efficacious ACP therapy in the near future.

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Section: Classification Of Acpsmentioning

confidence: 99%

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

2020

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“…On the other side, so-called cancer-targeting or anticancer peptides (ACPs) have been reported [96], which are, owing to their specific nature, attracted by the specific phenotypes of cancer cells and their surroundings. In fact, cancer cells differ from healthy cells since they display more negatively charged cell surface components, including also negatively charged headgroups of the lipid bilayer forming phospholipids.…”

Section: Cancer Targetingmentioning

confidence: 99%

Nanoparticles Modified with Cell-Penetrating Peptides: Conjugation Mechanisms, Physicochemical Properties, and Application in Cancer Diagnosis and Therapy

Gessner

Neundorf

2020

IJMS

155

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Based on their tunable physicochemical properties and the possibility of producing cell-specific platforms through surface modification with functional biomolecules, nanoparticles (NPs) represent highly promising tools for biomedical applications. To improve their potential under physiological conditions and to enhance their cellular uptake, combinations with cell-penetrating peptides (CPPs) represent a valuable strategy. CPPs are often cationic peptide sequences that are able to translocate across biological membranes and to carry attached cargos inside cells and have thus been recognized as versatile tools for drug delivery. Nevertheless, the conjugation of CPP to NP surfaces is dependent on many properties from both individual components, and further insight into this complex interplay is needed to allow for the fabrication of highly stable but functional vectors. Since CPPs per se are nonselective and enter nearly all cells likewise, additional decoration of NPs with homing devices, such as tumor-homing peptides, enables the design of multifunctional platforms for the targeted delivery of chemotherapeutic drugs. In this review, we have updated the recent advances in the field of CPP-NPs, focusing on synthesis strategies, elucidating the influence of different physicochemical properties, as well as their application in cancer research.

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“…Interestingly, many antimicrobial peptides exhibit anti-cancer activity, and indeed, such anti-cancer peptides (ACPs) may provide a promising, new approach in chemotherapy 24,25 . ACPs are usually cationic and therefore, attracted by the more negatively charged cell membrane of cancerous cells 26,27 .…”

Section: Introductionmentioning

confidence: 99%

Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity

Drexelius

Reinhardt

Grabeck

et al. 2021

Biochemical Journal

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Multidrug resistant (MDR) bacteria have adapted to most clinical antibiotics and are a growing threat to human health. One promising type of candidates for the everlasting demand of new antibiotic compounds constitute antimicrobial peptides (AMPs). These peptides act against different types of microbes by permeabilizing pathogen cell membranes, whereas being harmless to mammalian cells. Contrarily, another class of membrane-active peptides, namely cell-penetrating peptides (CPPs), is known to translocate in eukaryotic cells without substantially affecting the cell membrane. Since CPPs and AMPs share several physicochemical characteristics, we hypothesized if we can rationally direct the activity of a CPP towards antimicrobial activity. Herein, we describe the screening of a synthetic library, based on the CPP sC18, including structure-based design to identify the active residues within a CPP sequence and to discover novel AMPs with high activity. Peptides with increased hydrophobicity were tested against various bacterial strains, and hits were further optimized leading to four generations of peptides, with the last also comprising fluorinated amino acid building blocks. Interestingly, beside strong antibacterial activities, we also detected activity in cancer cells, while non-cancerous cells remained unharmed. The results highlight our new candidates, particularly those from generation 4, as a valuable and promising source for the development of future therapeutics with antibacterial activity and beyond.

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In silico design and optimization of selective membranolytic anticancer peptides

Cited by 55 publications

References 44 publications

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

Nanoparticles Modified with Cell-Penetrating Peptides: Conjugation Mechanisms, Physicochemical Properties, and Application in Cancer Diagnosis and Therapy

Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity

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