Structure‐activity relationship study of anoplin

Ifrah, Dan; Doisy, Xavier; Ryge, Trine S.; Pb, Hansen

doi:10.1002/psc.598

Cited by 49 publications

(65 citation statements)

References 45 publications

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“…Freshly drawn human erythrocytes in CPD (citrate-phosphatedextrose) buffer were obtained from the Copenhagen University Hospital blood bank (Copenhagen). Ifrah et al (2005). MALDI-TOF-MS was done on a VG Tof Spec E Fisons instrument (Fisons Instruments), using a-cyano-p-hydroxycinnamic acid as matrix.…”

Section: Chemicals and Materialsmentioning

confidence: 99%

“…Protected amino acids were coupled in fourfold excess employing a protocol using HATU/DIEA (1:1.5) activation as described by Ryge et al (2004). Cleavage and deprotecting were carried out using reagent L: TFA/TIS/DTT/H 2 O (88:2:5:5) for 2 h. The final workup was performed as described by Ifrah et al (2005). The peptide products were purified by preparative HPLC and lyophilized, and the masses were verified by MALDI TOF-MS.…”

Section: Chemicals and Materialsmentioning

confidence: 99%

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Structure–activity study of the antibacterial peptide fallaxin

et al. 2007

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Fallaxin is a 25-mer antibacterial peptide amide, which was recently isolated from the West Indian mountain chicken frog Leptodactylus fallax. Fallaxin has been shown to inhibit the growth of several Gram-negative bacteria including Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Here, we report a structure-activity study of fallaxin based on 65 analogs, including a complete alanine scan and a full set of N-and C-terminal truncated analogs. The fallaxin analogs were tested for hemolytic activity and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate resistant S. aureus, (VISA), methicillinsusceptible S. aureus (MSSA), E. coli, K. pneumoniae, and P. aeruginosa. We identified several analogs, which showed improved antibacterial activity compared to fallaxin. Our best candidate was FA12, which displayed MIC values of 3.12, 25, 25, and 50 mM against E. coli, K. pneumoniae, MSSA, and VISA, respectively. Furthermore, we correlated the antibacterial activity with various structural parameters such as charge, hydrophobicity AEHae, mean hydrophobic moment AEm H ae, and a-helicity. We were able to group the active and inactive analogs according to mean hydrophobicity AEHae and mean hydrophobic moment AEm H ae. Far-UV CD-spectroscopy experiments on fallaxin and several analogs in buffer, in TFE, and in membrane mimetic environments (small unilamellar vesicles) indicated that a coiled-coil conformation could be an important structural trait for antibacterial activity. This study provides data that support fallaxin analogs as promising lead structures in the development of new antibacterial agents.Keywords: alanine scan; antibacterial activity; coiled-coil conformation; fallaxin; solid-phase peptide synthesis Reprint requests to: Paul Robert Hansen, Department of Natural Sciences, Faculty of Life Sciences, University of Copenhagen, 1871 Frederiksberg C, Denmark; e-mail: prh@life.ku.dk; fax: 45-35332398.Abbreviations: ACTH, adrenocorticotropic hormone; ATCC, American type culture collection; Boc, tert-butyloxycarbonyl; BSA: bovine serum albumin; CFU, colony forming unit; CPD, citrate-phosphatedextrose; DIEA, diisopropylethylamine; DMPC, 1,2-dimyristoyl-snglycero-3-phosphocholine; DMPG, 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol; DTT: dithiothrethiol; Fmoc: 9-fluorenylmethoxy; AEHae, mean hydrophobicity; HC 50 : the toxin concentration yielding 50% lysis of a 1% suspension of erythrocytes after 45 min at 37°C; AEm H ae, mean hydrophobic moment; HATU, (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); HOBt, 1-hydroxybenzotriazole; MALDI-TOF MS, matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry; MIC, minimum inhibitory concentration; NMP, N-methyl-2-pyrrolidone; SUV, small unilamellar vesicles; TFA, trifluoroacetic acid; TFE, trifluoroethanol; TIS, triisopropylsilane; Trt, triphenylmethyl.Article and publication are at

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Section: Chemicals and Materialsmentioning

confidence: 99%

Section: Chemicals and Materialsmentioning

confidence: 99%

Structure–activity study of the antibacterial peptide fallaxin

et al. 2007

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“…The peptide was discovered by Konno et al (12) and is a decapeptide amide found in the venom of the Japanese solitary spider wasp (Anoplius samariensis). Amino acid positions that are important for anoplin activity have been identified by a substitution and truncation study (13). This generally showed that replacement of a hydrophilic amino acid with a hydrophobic one increased both antimicrobial activity and hemolysis.…”

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confidence: 99%

“…Several laboratories have shown that disrupting the ␣-helix propensity by insertion of a central D-form amino acid decreases hemolytic activity more than it decreases antimicrobial potency (15)(16)(17)(18)(19)(20)(21)(22). Other approaches include modification of the termini (23,24), modification of the charge and hydrophobicity (13,14,(25)(26)(27), retro and inverso synthesis (24), as well as cyclization (28).…”

mentioning

confidence: 99%

“…1), using anoplin as an example. Amino acid positions 2, 5, 6, 8, and 10 in anoplin have been identified to be possible sites of side chain optimization (13,14), and use of the D enantiomer in position 6 was also tested. We defined these modifications as a 2 6 -peptide, or 64-peptide, matrix and searched the matrix for peptides with desirable antimicrobial properties.…”

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Novel Method To Identify the Optimal Antimicrobial Peptide in a Combination Matrix, Using Anoplin as an Example

Munk

Ritz

Fliedner

et al. 2014

Antimicrob Agents Chemother

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cMicrobial resistance is an increasing health concern and a true danger to human well-being. A worldwide search for new compounds is ongoing, and antimicrobial peptides are promising lead candidates for tomorrow's antibiotics. The decapeptide anoplin (GLLKRIKTLL-NH 2 ) is an especially interesting candidate because of its small size as well as its antimicrobial and nonhemolytic properties. Optimization of the properties of an antimicrobial peptide such as anoplin requires multidimensional searching in a complex chemical space. Typically, such optimization is performed by labor-intensive and costly trial-and-error methods. In this study, we show the benefit of fractional factorial design for identification of the optimal antimicrobial peptide in a combination matrix. We synthesized and analyzed a training set of 12 anoplin analogs, representative of 64 analogs in total. Using MIC, hemolysis, and high-performance liquid chromatography retention time data, we constructed analysis-of-variance models that describe the relationship between these properties and the structural characteristics of the analogs. We show that the mathematical models derived from the training set data can be used to predict the properties of other analogs in the chemical space. Hence, this method provides an efficient means of identification of the optimal peptide in the searched chemical space.

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Peptide Stapling by Crosslinking Two Amines with α‐Ketoaldehydes through Diverse Modified Glyoxal‐Lysine Dimer Linkers

Guo,

Chu,

et al. 2024

Angewandte Chemie

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α‐Ketoaldehydes play versatile roles in the ubiquitous natural processes of protein glycation. However, leveraging the reactivity of α‐ketoaldehydes for biomedical applications has been challenging. Previously, the reactivity of α‐ketoaldehydes with guanidine has been harnessed to design probes for labeling Arg residues on proteins in an aqueous medium. Herein, a highly effective, broadly applicable, and operationally simple protocol for stapling native peptides by crosslinking two amino groups through diverse imidazolium linkers with various α‐ketoaldehyde reagents is described. The use of hexafluoroisopropanol as a solvent facilitates rapid and clean reactions under mild conditions and enables unique selectivity for Lys over Arg. The naturally occurring GOLD/MOLD linkers have been expanded to encompass a wide range of modified glyoxal‐lysine dimer (OLD) linkers. In a proof‐of‐concept trial, these modular stapling reactions enabled a convenient two‐round strategy to streamline the structure‐activity relationship (SAR) study of the wasp venom peptide anoplin, leading to enhanced biological activities.

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Structure‐activity relationship study of anoplin

Cited by 49 publications

References 45 publications

Structure–activity study of the antibacterial peptide fallaxin

Structure–activity study of the antibacterial peptide fallaxin

Novel Method To Identify the Optimal Antimicrobial Peptide in a Combination Matrix, Using Anoplin as an Example

Peptide Stapling by Crosslinking Two Amines with α‐Ketoaldehydes through Diverse Modified Glyoxal‐Lysine Dimer Linkers

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