Structural Dissection of Crotalicidin, a Rattlesnake Venom Cathelicidin, Retrieves a Fragment with Antimicrobial and Antitumor Activity

Falcão, Cláudio Borges; Pérez‐Peinado, Clara; Torre, Beatriz G. de la; Mayol, Xavier; Zamora-Carreras, Héctor; Jiménez, María Ángeles Sánchez; Rádis‐Baptista, Gandhi; Andreu, David

doi:10.1021/acs.jmedchem.5b01142

Cited by 63 publications

(87 citation statements)

References 60 publications

(96 reference statements)

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“…Sequences of Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and analogs were submitted to the PSIPRED v3.3 (http://bioinf.cs.ucl.ac.uk/psipred/) 38 web server to predict secondary structure propensity. For 3D structure prediction, the PEP-FOLD3 web server (http://bioserv.rpbs.univ-paris-diderot.fr/services/ PEP-FOLD3/#usage) 39 was accessed, and the best five models (lowest OPEP [optimized potential for efficient structure prediction] energy) were superposed and represented using the PyMOL Molecular Graphical System, Version 2.0.…”

Section: Simulation Of Peptide Structurementioning

confidence: 99%

Structural determinants conferring unusual long life in human serum to rattlesnake‐derived antimicrobial peptide Ctn[15‐34]

Pérez‐Peinado

Dias

Mendonça

et al. 2019

Journal of Peptide Science

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Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], a downsized version of the snake venom cathelicidin-like peptide crotalicidin (Ctn), shows an unusually high lifespan (t 1/2 , approximately 12 h) in human serum, which significantly adds to its promise as an antimicrobial and antitumor agent. Herein we investigate the role of Ctn[15-34] structure on serum survival. Using a set of analogs, we show that C-terminal amidation, as well as the specific layout of the Ctn[15-34] sequence-a helical N-terminal domain followed by a hydrophobic domain-is crucial for slow degradation, and any change in their arrangement results in significantly lower t 1/2 . Aside from the privileged primary structure, features such as self-aggregation can be ruled out as causes for the long serum life. Instead, studies in other protease-rich fluids suggest a key role for certain human serum components. Finally, we demonstrate that Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] is able to induce bacterial death even after 12-hour pre-incubation in serum, in agreement with the proteolytic data. Altogether, the results shed light on the uncommon stability of Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] in human serum and confirm its potential as an antiinfective lead.

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Section: Simulation Of Peptide Structurementioning

confidence: 99%

Structural determinants conferring unusual long life in human serum to rattlesnake‐derived antimicrobial peptide Ctn[15‐34]

Pérez‐Peinado

Dias

Mendonça

et al. 2019

Journal of Peptide Science

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“…Good agreement between the proposed NMR and predicted structures was also found for longer peptides that showed clear curvature in the proposed experimental structure, for example magainin-2 (PDB: 2MAG [68]), crotalicidin (PDB: 2MWT [85]) and LL-37 (PDB: 2K6O [89]). Again in a number of cases, the predicted structures showed greater curvature than that proposed based on the NMR data, especially at low mutation rates, for example LL-23 (PDB: 2LMF [67]) and CAP18 (PDB: 1LYP [87]).…”

Section: Validation and Testing Of The Asp Algorithmmentioning

confidence: 66%

“…The ASP algorithm was run with different values of the key parameters (hydrophobic scale, tournament size, and torsion mutation rate) on a selected subset of the systems in Table . The subset consisted of alyteserin‐1c (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=2L5R ), CAP18 (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=1LYP ), crotalicidin (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=2MWT ), GF‐17 (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=2L5M ), hylin a1 (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=2N0O ) and LL‐37 (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=2K6O ). These systems were selected so as to represent a range of sizes as well as linear and curved helices.…”

Section: Resultsmentioning

confidence: 99%

“…The ASP algorithm was run with different values of the key parameters (hydrophobic scale, tournament size, and torsion mutation rate) on a selected subset of the systems in Table 1. The subset consisted of alyteserin-1c (PDB: 2L5R [65]), CAP18 (PDB: 1LYP [87]), crotalicidin (PDB: 2MWT [85]), GF-17 (PDB: 2L5M [56]), hylin a1 (PDB: 2N0O [57]) and LL-37 (PDB: 2K6O [89]). These systems were selected so as to represent a range of sizes as well as linear and curved helices.…”

Section: Resultsmentioning

confidence: 99%

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Curved or linear? Predicting the 3‐dimensional structure of α‐helical antimicrobial peptides in an amphipathic environment

et al. 2019

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α‐Helical membrane‐active antimicrobial peptides (AMPs) are known to act via a range of mechanisms, including the formation of barrel‐stave and toroidal pores and the micellisation of the membrane (carpet mechanism). Different mechanisms imply that the peptides adopt different 3D structures when bound at the water–membrane interface, a highly amphipathic environment. Here, an evolutionary algorithm is used to predict the 3D structure of a range of α‐helical membrane‐active AMPs at the water–membrane interface by optimising amphipathicity. This amphipathic structure prediction (ASP) is capable of distinguishing between curved and linear peptides solved experimentally, potentially allowing the activity and mechanism of action of different membrane‐active AMPs to be predicted. The ASP algorithm is accessible via a web interface at ://atb.uq.edu.au/asp/.

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“…These peptides show potent broad spectrum activity against microorganisms that include Gram-negative and Gram-positive bacteria, enveloped viruses, fungi and even cancerous cells and display potential for their future development as novel therapeutic agents345678910.…”

mentioning

confidence: 99%

Piscidin-1-analogs with double L- and D-lysine residues exhibited different conformations in lipopolysaccharide but comparable anti-endotoxin activities

Kumar

Mahajan

Awasthi

et al. 2017

Sci Rep

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To become clinically effective, antimicrobial peptides (AMPs) should be non-cytotoxic to host cells. Piscidins are a group of fish-derived AMPs with potent antimicrobial and antiendotoxin activities but limited by extreme cytotoxicity. We conjectured that introduction of cationic residue(s) at the interface of polar and non-polar faces of piscidins may control their insertion into hydrophobic mammalian cell membrane and thereby reducing cytotoxicity. We have designed several novel analogs of piscidin-1 by substituting threonine residue(s) with L and D-lysine residue(s). L/D-lysine-substituted analogs showed significantly reduced cytotoxicity but exhibited either higher or comparable antibacterial activity akin to piscidin-1. Piscidin-1-analogs demonstrated higher efficacy than piscidin-1 in inhibiting lipopolysaccharide (LPS)-induced pro-inflammatory responses in THP-1 cells. T15,21K-piscidin-1 (0.5 mg/Kg) and T15,21dK-piscidin-1 (1.0 mg/Kg) demonstrated 100% survival of LPS (12.0 mg/Kg)-administered mice. High resolution NMR studies revealed that both piscidin-1 and T15,21K-piscidin-1 adopted helical structures, with latter showing a shorter helix, higher amphipathicity and cationic residues placed at optimal distances to form ionic/hydrogen bond with lipid A of LPS. Remarkably, T15,21dK-piscidin-1 showed a helix-loop-helix structure in LPS and its interactions with LPS could be sustained by the distance of separation of side chains of R7 and D-Lys-15 which is close to the inter-phosphate distance of lipid A.

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Structural Dissection of Crotalicidin, a Rattlesnake Venom Cathelicidin, Retrieves a Fragment with Antimicrobial and Antitumor Activity

Cited by 63 publications

References 60 publications

Structural determinants conferring unusual long life in human serum to rattlesnake‐derived antimicrobial peptide Ctn[15‐34]

Structural determinants conferring unusual long life in human serum to rattlesnake‐derived antimicrobial peptide Ctn[15‐34]

Curved or linear? Predicting the 3‐dimensional structure of α‐helical antimicrobial peptides in an amphipathic environment

Piscidin-1-analogs with double L- and D-lysine residues exhibited different conformations in lipopolysaccharide but comparable anti-endotoxin activities

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