Antimicrobial activity of doubly-stapled alanine/lysine-based peptides

Dinh, Thuy T. T.; Kim, Do-Hee; Xuan, Huy Luong; Lee, Bong-Jin; Kim, Young Woo

doi:10.1016/j.bmcl.2015.06.053

Cited by 42 publications

(40 citation statements)

References 26 publications

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“…In fact, more than 85% of Ac-DS-14W remained intact after 60 min of trypsin digestion, whereas single-stapled and unstapled counterparts were completely digested. Overall, in contrast to Chapuis et al, this study demonstrates that double-stapling, as far as appropriate sequences are applied, may improve peptide pharmacological properties [ 35 , 42 ].…”

Section: Hydrocarbon Stapled Antimicrobial Peptidescontrasting

confidence: 72%

Hydrocarbon Stapled Antimicrobial Peptides

2018

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Antimicrobial peptides are promising candidates for anti-infective pharmaceuticals. Unfortunately, because of their low proteolytic and chemical stability, their usage is generally narrowed down to topical formulations. Until now, numerous approaches to increase peptide stability have been proposed. One of them, peptide hydrocarbon stapling, a modification based on stabilizing peptide secondary structure with a side-chain covalent hydrocarbon bridge, have been successfully applied to many peptides. Moreover, constraining secondary structure of peptides have also been proven to increase their biological activity. This review article describes studies on hydrocarbon stapled antimicrobial peptides with respect to improved drug-like properties.

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Section: Hydrocarbon Stapled Antimicrobial Peptidescontrasting

confidence: 72%

Hydrocarbon Stapled Antimicrobial Peptides

2018

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“…[57][58][59] In these cases, the two crosslinks were separated by a large number of amino acids or located at different faces of the helix to avoid potential cross-reactivity. [57][58][59][60][61] In comparison to these studies, in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Since Rab GTPases are intracellular proteins, robust cellular uptake is essential for potential modulators of Rab activity and localization. For this reason, subsequent sequence variation focused on the reduction of negatively charged amino acid side chains as they are implicated in the prevention of cellular uptake (net charge of StRIP14: -3.9).…”

Section: Discussionmentioning

confidence: 90%

Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

et al. 2016

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Small GTPases comprise a family of highly relevant targets in chemical biology and medicinal chemistry research and have been considered "undruggable" due to the persisting lack of effective synthetic modulators and suitable binding pockets. As molecular switches, small GTPases control a multitude of pivotal cellular functions, and their dysregulation is associated with many human diseases such as various forms of cancer. Rab-GTPases represent the largest subfamily of small GTPases and are master regulators of vesicular transport interacting with various proteins via flat and extensive protein-protein interactions (PPIs). The only reported synthetic inhibitor of a PPI involving an activated Rab GTPase is the hydrocarbon stapled peptide StRIP3. However, this macrocyclic peptide shows low proteolytic stability and cell permeability. Here, we report the design of a bioavailable StRIP3 analogue that harbors two hydrophobic cross-links and exhibits increased binding affinity, combined with robust cellular uptake and extremely high proteolytic stability. Localization experiments reveal that this double-stapled peptide and its target protein Rab8a accumulate in the same cellular compartments. The reported approach offers a strategy for the implementation of biostability into conformationally constrained peptides while supporting cellular uptake and target affinity, thereby conveying drug-like properties.

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“…Peptides that mimic the HicBA complex have greater ability to inhibit the interaction between toxin and antitoxin independent of the concentration of peptide than other TA-complex-mimicking peptides ( 48 , 49 , 96 ). Furthermore, the MIC of the tested peptides could be obtained via an antimicrobial activity test, despite its relatively high value compared with that of other highly engineered antimicrobial peptides ( 74 , 97 ). The fact that the antimicrobial activity of peptides with higher α-helical content and better folding was greater ( Supplementary Figure S6C ) suggests that we might be able to obtain a more optimized inhibitor by modifying the peptide using conjugation strategies and surface modulation such as stapling the peptides via hydrocarbon cross-linking to obtain better permeability and structural folding ( 98 , 99 ).…”

Section: Discussionmentioning

confidence: 99%

Functional insights into the Streptococcus pneumoniae HicBA toxin–antitoxin system based on a structural study

Kim

Kang

Park

et al. 2018

Nucleic Acids Research

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Streptococcus pneumonia has attracted increasing attention due to its resistance to existing antibiotics. TA systems are essential for bacterial persistence under stressful conditions such as nutrient deprivation, antibiotic treatment, and immune system attacks. In particular, S. pneumoniae expresses the HicBA TA gene, which encodes the stable HicA toxin and the labile HicB antitoxin. These proteins interact to form a non-toxic TA complex under normal conditions, but the toxin is activated by release from the antitoxin in response to unfavorable growth conditions. Here, we present the first crystal structure showing the complete conformation of the HicBA complex from S. pneumonia. The structure reveals that the HicA toxin contains a double-stranded RNA-binding domain that is essential for RNA recognition and that the C-terminus of the HicB antitoxin folds into a ribbon-helix-helix DNA-binding motif. The active site of HicA is sterically blocked by the N-terminal region of HicB. RNase activity assays show that His36 is essential for the ribonuclease activity of HicA, and nuclear magnetic resonance (NMR) spectra show that several residues of HicB participate in binding to the promoter DNA of the HicBA operon. A toxin-mimicking peptide that inhibits TA complex formation and thereby increases toxin activity was designed, providing a novel approach to the development of new antibiotics.

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Antimicrobial activity of doubly-stapled alanine/lysine-based peptides

Cited by 42 publications

References 26 publications

Hydrocarbon Stapled Antimicrobial Peptides

Hydrocarbon Stapled Antimicrobial Peptides

Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

Functional insights into the Streptococcus pneumoniae HicBA toxin–antitoxin system based on a structural study

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