Design and synthesis of cyclic disulfide-bonded antibacterial peptides on the basis of the α helical domain of Tenecin 1, an insect defensin

Ahn, Hyun Young; Won-Mi, Cho; Kim, Joungmin; Joshi, Bishnu P.; Park, Jun-won; Lohani, Chuda Raj; Cho, Hyeongjin; Lee, Keun‐Hyeung

doi:10.1016/j.bmc.2008.01.019

Cited by 14 publications

(7 citation statements)

References 35 publications

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“…Because of their constrained geometries, cyclic peptides often generate more bioactive compounds with prolonged biological activity. − Nevertheless, this is not always the case because cyclization limits structural flexibility and might occasionally fail to retain activity . While cyclization is a simple approach to improving stability and enhancing bioactivity, cyclization might prevent peptides from achieving bioactive conformations or could lead to more selective antimicrobial analogues. , HDPs are well known to have complex multimodal mechanisms of action including altering cytoplasmic and outer membrane permeability and inhibiting cell division, cell wall biosynthesis, enzymatic activities, etc. ,, IDR-1018 is a unique multifunctional molecule with not only direct (moderate) antibacterial activity, but also the ability to suppress biofilm formation and to induce the dissolution of mature biofilms . Previous studies showed a favorable activity of IDR-1018 toward bacterial biofilms because of its ability to bind the second-messenger nucleotide (p)ppGpp and stimulate its degradation in stressed cells within 30 min. , This nucleotide is part of the stringent stress response in bacteria and essential in biofilm development .…”

Section: Resultsmentioning

confidence: 99%

“…25 While cyclization is a simple approach to improving stability and enhancing bioactivity, cyclization might prevent peptides from achieving bioactive conformations or could lead to more selective antimicrobial analogues. 26,27 HDPs are well known to have complex multimodal mechanisms of action including altering cytoplasmic and outer membrane permeability and inhibiting cell division, cell wall biosynthesis, enzymatic activities, etc. 4,28,29 IDR-1018 is a unique multifunctional molecule with not only direct (moderate) antibacterial activity, but also the ability to suppress biofilm formation and to induce the dissolution of mature biofilms.…”

Section: ■ Introductionmentioning

confidence: 99%

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Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity

et al. 2020

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Host-defense peptides have drawn significant attention as new drugs or drug adjuvants to combat multidrug-resistant bacteria. In this study, we report the development of cyclic derivatives of the immunomodulatory and antibiofilm innate defense regulator peptide (IDR)-1018 based on three different synthetic strategies including head-to-tail cyclization (C1), side-chain-to-tail cyclization (C2), and a disulfide bond cross-linkage (C3). The generated mimetics showed enhanced proteolytic stability and reduced aggregation in vitro and in vivo. The C2 derivative exhibited exceptional ability to suppress inflammation and significantly reduce bacterial loads in a high-density Staphylococcus aureus murine skin infection model. The findings describe different routes to the creation of enzymatically stable mimetics of IDR-1018 and identify a promising new cyclic analogue against bacterial infections.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity

et al. 2020

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“…As such, chemical approaches to cyclic homodetic (cyclization through an amide bond) or heterodetic (cyclization through a non‐amide bond) head‐to‐tail, head/tail‐to‐side chain, side chain‐to‐side chain peptides (Figure ) have deserved special attention from peptide chemists (Davies, ; Lambert, Mitchell, & Roberts, ; Martí‐Centelles, Pandey, Burguete, & Luis, ; Tam & Wong, ; White & Yudin, ). One classical route is oxidation of thiol groups to produce a disulfide bridge between the side chains of Cys residues, which may either belong or be added to the original sequence; this is relatively simple from a synthetic viewpoint if only one disulfide bridge is to be formed (Ahn et al, ), but can be laborious if multiple disulfide bridges are targeted, although improved methods have been emerging over the past 15 years (e.g., Cheneval et al, ; Vila‐Perelló, Sánchez‐Vallet, García‐Olmedo, Molina, & Andreu, ). One limitation of disulfide‐bridged peptides is their lability to bioreducing conditions (Yang, Chen, Vlahov, Cheng, & Low, ), which has often led researchers to invest on homodetic cyclic peptides, given the higher chemical and biochemical stability of amide bonds (Monaim et al, ; Rohrbacher, Deniau, Luther, & Bode, ; Valldosera et al, ).…”

Section: Peptides As Drugs: Challenges and Perspectivesmentioning

confidence: 99%

Harnessing snake venom phospholipases A₂ to novel approaches for overcoming antibiotic resistance

Almeida

Palacios

Patiño

et al. 2018

Drug Development Research

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The emergence of antibiotic resistance drives an essential race against time to reveal new molecular structures capable of addressing this alarming global health problem. Snake venoms are natural catalogs of multifunctional toxins and privileged frameworks, which serve as potential templates for the inspiration of novel treatment strategies for combating antibiotic resistant bacteria. Phospholipases A2 (PLA2s) are one of the main classes of antibacterial biomolecules, with recognized therapeutic value, found in these valuable secretions. Recently, a number of biomimetic oligopeptides based on small fragments of primary structure from PLA2 toxins has emerged as a meaningful opportunity to overcome multidrug‐resistant clinical isolates. Thus, this review will highlight the biochemical and structural properties of antibacterial PLA2s and peptides thereof, as well as their possible molecular mechanisms of action and key roles in development of effective therapeutic strategies. Chemical strategies possibly useful to convert antibacterial peptides from PLA2s to efficient drugs will be equally addressed.

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“…[18][19][20][21] It is also a common approach to improve protease stability of peptides. [22][23][24] Therefore, we cyclized IL8RP-LoopsE to improve its properties. IL8RP-LoopsQ was cyclized as a control.…”

Section: Introductionmentioning

confidence: 99%

“…Cyclization leads to a more rigid structure and reduces the entropic penalty as the peptide binds to its target protein and thereby lowers the free binding energy 18–21 . It is also a common approach to improve protease stability of peptides 22–24 . Therefore, we cyclized IL8RP‐LoopsE to improve its properties.…”

Section: Introductionmentioning

confidence: 99%

Effect of macrocyclization and tetramethylrhodamine labeling on chemokine binding peptides

Wack

Brahm

Babel

et al. 2023

Journal of Peptide Science

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Receptor‐derived peptides have played an important role in elucidating chemokine‐receptor interactions. For the inflammatory chemokine CXC‐class chemokine ligand 8 (CXCL8), a site II‐mimetic peptide has been derived from parts of extracellular loops 2 and 3 and adjacent transmembrane helices of its receptor CXC‐class chemokine receptor 1 (Helmer et al., RSC Adv., 2015, 5, 25657). The peptide sequence with a C‐terminal glutamine did not bind to CXCL8, whereas one with a C‐terminal glutamate did but with low micromolar affinity. We sought to improve the affinity and protease stability of the latter peptide through cyclization while also cyclizing the former for control purposes. To identify a cyclization strategy that permits a receptor‐like interaction, we conducted a molecular dynamics simulation of CXCL8 in complex with full‐length CXC‐class chemokine receptor 1. We introduced a linker to provide an appropriate spacing between the termini and used an on‐resin side‐chain‐to‐tail cyclization strategy. Upon chemokine binding, the fluorescence intensity of the tetramethylrhodamine (TAMRA)‐labeled cyclic peptides increased whereas the fluorescence anisotropy decreased. Additional molecular dynamics simulations indicated that the fluorophore interacts with the peptide macrocycle so that chemokine binding leads to its displacement and observed changes in fluorescence. Macrocyclization of both 18‐amino acid‐long peptides led to the same low micromolar affinity for CXCL8. Likewise, both TAMRA‐labeled linear peptides interacted with CXCL8 with similar affinities. Interestingly, the linear TAMRA‐labeled peptides were more resistant to tryptic digestion than the unlabeled counterparts, whereas the cyclized peptides were not degraded at all. We conclude that the TAMRA fluorophore tends to interact with peptides altering their protease stability and behavior in fluorescence‐based assays.

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Design and synthesis of cyclic disulfide-bonded antibacterial peptides on the basis of the α helical domain of Tenecin 1, an insect defensin

Cited by 14 publications

References 35 publications

Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity

Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity

Harnessing snake venom phospholipases A₂ to novel approaches for overcoming antibiotic resistance

Effect of macrocyclization and tetramethylrhodamine labeling on chemokine binding peptides

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Design and synthesis of cyclic disulfide-bonded antibacterial peptides on the basis of the α helical domain of Tenecin 1, an insect defensin

Cited by 14 publications

References 35 publications

Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity

Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity

Harnessing snake venom phospholipases A2 to novel approaches for overcoming antibiotic resistance

Effect of macrocyclization and tetramethylrhodamine labeling on chemokine binding peptides

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Harnessing snake venom phospholipases A₂ to novel approaches for overcoming antibiotic resistance