Antimicrobial activity and stability of protonectin with<scp>D</scp>-amino acid substitutions

Qiu, Shuai; Zhu, Ranran; Zhao, Yanyan; An, Xiaoping; Jia, Fengjing; Peng, Jinxiu; Ma, Zhiqiang; Zhu, Yuan‐Yuan; Wang, Kairong; Su, Jinhuan; Wang, Qingjun; Wang, Hailin; Li, Yuan; Wang, Kairong; Yan, Wenjin; Wang, Rui

doi:10.1002/psc.2989

Cited by 27 publications

(26 citation statements)

References 35 publications

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“…In this regard, numerous strategies, such as peptide cyclization, side-chain modification, multimerization, drug delivery methods, and peptidomimetic approaches, have been found to display great potential for improving the in vivo application of synthetic AMPs (Ong et al, 2014). A useful approach for enhancing proteolytic stability is replacing the natural amino acids in AMPs with non-coded α-amino acid derivatives such as D-and unnatural amino acids (Kaminski and Feix, 2011;Di Grazia et al, 2015;Khara et al, 2016;Jia et al, 2017;Qiu et al, 2017;Sun et al, 2017;Zaet et al, 2017;Oliva et al, 2018). In this study, a series of peptide derivatives containing D-and unnatural amino acids were designed based on the previously reported cationic AMP Pep05.…”

Section: Discussionmentioning

confidence: 99%

D- and Unnatural Amino Acid Substituted Antimicrobial Peptides With Improved Proteolytic Resistance and Their Proteolytic Degradation Characteristics

Xia

et al. 2020

Front. Microbiol.

122

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The transition of antimicrobial peptides (AMPs) from the laboratory to market has been severely hindered by their instability toward proteases in biological systems. In the present study, we synthesized derivatives of the cationic AMP Pep05 (KRLFKKLLKYLRKF) by substituting L -amino acid residues with D - and unnatural amino acids, such as D- lysine, D- arginine, L- 2,4-diaminobutanoic acid (Dab), L- 2,3-diaminopropionic acid (Dap), L- homoarginine, 4-aminobutanoic acid (Aib), and L- thienylalanine, and evaluated their antimicrobial activities, toxicities, and stabilities toward trypsin, plasma proteases, and secreted bacterial proteases. In addition to measuring changes in the concentration of the intact peptides, LC-MS was used to identify the degradation products of the modified AMPs in the presence of trypsin and plasma proteases to determine degradation pathways and examine whether the amino acid substitutions afforded improved proteolytic resistance. The results revealed that both D- and unnatural amino acids enhanced the stabilities of the peptides toward proteases. The derivative DP06, in which all of the L- lysine and L- arginine residues were replaced by D -amino acids, displayed remarkable stability and mild toxicity in vitro but only slight activity and severe toxicity in vivo , indicating a significant difference between the in vivo and in vitro results. Unexpectedly, we found that the incorporation of a single Aib residue at the N-terminus of compound UP09 afforded remarkably enhanced plasma stability and improved activity in vivo . Hence, this derivative may represent a candidate AMP for further optimization, providing a new strategy for the design of novel AMPs with improved bioavailability.

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Section: Discussionmentioning

confidence: 99%

D- and Unnatural Amino Acid Substituted Antimicrobial Peptides With Improved Proteolytic Resistance and Their Proteolytic Degradation Characteristics

Xia

et al. 2020

Front. Microbiol.

122

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“…NIH-3T3 cells are mouse fibroblast cells suitable for transfection studies and can be used as a non-cancerous model for cytotoxicity studies [26]. Partial or entire D-amino acid substitution is reported as a useful approach to develop better therapeutic activities, to increase the resistance to proteolysis and to overcome many hurdles faced by host defense peptides [30,31]. In the current study, the stereochemically more flexible achiral glycine residues at positions 4, 7 and/or 10 of temporin-SHa, were substituted with D-Ala residues to obtain several analogs [G4a]SHa,…”

Section: Cell Lines and Materialsmentioning

confidence: 99%

Synthesis of breast cancer targeting conjugate of temporin-SHa analog and its effect on pro- and anti-apoptotic protein expression in MCF-7 cells

et al. 2018

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The frog natural product temporin-SHa (FLSGIVGMLGKLF) is a potent antimicrobial peptide, as is the analog [S3K]SHa. By solid-phase synthesis, we prepared temporin-SHa and several temporin-SHa analogs with one or more D-alanine residues incorporated. The natural product and the analog [G10a]SHa were found to be cytotoxic in mammalian cell lines and induce cell death. To achieve selectivity, we conjugated the analog [G10a]SHa with a breast cancer targeting peptide (BCTP). The resulting peptide temporin [G10a]SHa-BCTP conjugate was selectively active against the MCF-7 breast cancer cell line with no cytotoxicity in NIH-3T3 fibroblasts. Unlike the natural product or [G10a]SHa, the conjugated peptide induced apoptosis, downregulating the expression of Bcl-2 and survivin and upregulating Bax and caspase-3.

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“…[18] Studies with the chemotactic peptide protonectin identified potent antifungal and antibacterial activity. [15,19] Notably, protonectin did not show hemolytic activity, a desirable characteristic for a potential drug lead. Recent studies were directed at modifying the sequence of protonectin to increase resistance against proteases and improve its biological activity.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial and Anticancer Properties of Synthetic Peptides Derived from the Wasp Parachartergus fraternus

et al. 2021

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Agelaia-MPI and protonectin are antimicrobial peptides isolated from the wasp Parachartergus fraternus that show antimicrobial and neuroactive activities. Previously, two analogues of these peptides, neuroVAL and protonectin-F, were designed to reduce nonspecific toxicity and improve potency. Here, the threedimensional structures of neuroVAL, protonectin and protonectin-F were determined by using circular dichroism and NMR spectroscopy. Antibacterial, antifungal, cytotoxic and hemolytic activities were tested for the parent peptides and analogues. All peptides showed moderate antimicrobial activity against Gram-positive bacteria, with agelaia-MPI being the most active. Protonectin and protonectin-F were found to be toxic to cancerous and noncancerous cell lines. Internalization experiments revealed that these peptides accumulate inside both cell types. By contrast, neuroVAL was nontoxic to all tested cells and was able to enter cells without accumulating. In summary, neuroVAL has potential as a nontoxic cell-penetrating peptide, while protonectin-F needs further modification to realize its potential as an antitumor peptide.

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Antimicrobial activity and stability of protonectin withD-amino acid substitutions

Cited by 27 publications

References 35 publications

D- and Unnatural Amino Acid Substituted Antimicrobial Peptides With Improved Proteolytic Resistance and Their Proteolytic Degradation Characteristics

D- and Unnatural Amino Acid Substituted Antimicrobial Peptides With Improved Proteolytic Resistance and Their Proteolytic Degradation Characteristics

Synthesis of breast cancer targeting conjugate of temporin-SHa analog and its effect on pro- and anti-apoptotic protein expression in MCF-7 cells

Antimicrobial and Anticancer Properties of Synthetic Peptides Derived from the Wasp Parachartergus fraternus

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