Rational Design of Alpha‐Helical Antimicrobial Peptides: Do's and Don'ts

Uggerhøj, Lars Erik; Poulsen, Tanja Juul; Munk, J.; Fredborg, Marlene; Søndergaard, Teis Esben; Frimodt‐Møller, Niels; Hansen, Paul Robert; Wimmer, Reinhard

doi:10.1002/cbic.201402581

Cited by 63 publications

(58 citation statements)

References 35 publications

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“…That the bacterial plasma membrane is a primary target of AMP became a dogma [93][94][95][96][97][98][99][100]. However, a necessity to switch from the studies of AMP in model membrane systems to their investigations on cells is becoming clear [101,102].…”

Section: Biological Effects Antibacterial Activitymentioning

confidence: 99%

Latarcins: versatile spider venom peptides

Dubovskii

Vassilevski

Kozlov

et al. 2015

Cell. Mol. Life Sci.

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Arthropod venoms feature the presence of cytolytic peptides believed to act synergetically with neurotoxins to paralyze prey or deter aggressors. Many of them are linear, i.e., lack disulfide bonds. When isolated from the venom, or obtained by other means, these peptides exhibit common properties. They are cationic; being mostly disordered in aqueous solution, assume amphiphilic α-helical structure in contact with lipid membranes; and exhibit general cytotoxicity, including antifungal, antimicrobial, hemolytic, and anticancer activities. To suit the pharmacological needs, the activity spectrum of these peptides should be modified by rational engineering. As an example, we provide a detailed review on latarcins (Ltc), linear cytolytic peptides from Lachesana tarabaevi spider venom. Diverse experimental and computational techniques were used to investigate the spatial structure of Ltc in membrane-mimicking environments and their effects on model lipid bilayers. The antibacterial activity of Ltc was studied against a panel of Gram-negative and Gram-positive bacteria. In addition, the action of Ltc on erythrocytes and cancer cells was investigated in detail with confocal laser scanning microscopy. In the present review, we give a critical account of the progress in the research of Ltc. We explore the relationship between Ltc structure and their biological activity and derive molecular characteristics, which can be used for optimization of other linear peptides. Current applications of Ltc and prospective use of similar membrane-active peptides are outlined.

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Section: Biological Effects Antibacterial Activitymentioning

confidence: 99%

Latarcins: versatile spider venom peptides

Dubovskii

Vassilevski

Kozlov

et al. 2015

Cell. Mol. Life Sci.

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“…With respect to this, many NMR experiments use solutions of the peptide in the presence of micelles of amphipathic molecules, whose role is to mimic the membrane. The PDB entry 2MJT, which corresponds to the NMR-derived conformation of the antimicrobial peptide Anoplin in the presence of dodecylphosphocholine (DPC) micelles, was selected as a model system to validate our molecular dynamics simulations setup [11]. …”

Section: Discussionmentioning

confidence: 99%

“…The next step was to design an in silico system reproducing the same conditions in which the NMR experiment had been conducted [11]. The same MD protocol was therefore applied to an artificially built system, containing the micelle, the extended peptide built from scratch and the phosphate buffer.…”

Section: Discussionmentioning

confidence: 99%

“…The NMR structure of Anoplin combined with dodecylphosphocholine (DPC) micelle is available as PDB entry 2MJT [11]. In order to test the suitability of this system and of the software used, 2MJT PDB file was initially downloaded (including the micelle).…”

Section: Methodsmentioning

confidence: 99%

“…A 10 ns MD simulation was conducted using Desmond and OPLS2005 force field (Maestro version 11.0.014, Schrödinger LLC, New York, NY, USA). This was followed by a set of MD simulations on a system built to recreate the experimental conditions described by Uggerhoj [11]. Therefore, a micelle formed by 65 DPC molecules was initially built using Packmol [28].…”

Section: Methodsmentioning

confidence: 99%

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In Silico Structural Evaluation of Short Cationic Antimicrobial Peptides

et al. 2018

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Cationic peptides with antimicrobial properties are ubiquitous in nature and have been studied for many years in an attempt to design novel antibiotics. However, very few molecules are used in the clinic so far, sometimes due to their complexity but, mostly, as a consequence of the unfavorable pharmacokinetic profile associated with peptides. The aim of this work is to investigate cationic peptides in order to identify common structural features which could be useful for the design of small peptides or peptido-mimetics with improved drug-like properties and activity against Gram negative bacteria. Two sets of cationic peptides (AMPs) with known antimicrobial activity have been investigated. The first reference set comprised molecules with experimentally-known conformations available in the protein databank (PDB), and the second one was composed of short peptides active against Gram negative bacteria but with no significant structural information available. The predicted structures of the peptides from the first set were in excellent agreement with those experimentally-observed, which allowed analysis of the structural features of the second group using computationally-derived conformations. The peptide conformations, either experimentally available or predicted, were clustered in an “all vs. all” fashion and the most populated clusters were then analyzed. It was confirmed that these peptides tend to assume an amphipathic conformation regardless of the environment. It was also observed that positively-charged amino acid residues can often be found next to aromatic residues. Finally, a protocol was evaluated for the investigation of the behavior of short cationic peptides in the presence of a membrane-like environment such as dodecylphosphocholine (DPC) micelles. The results presented herein introduce a promising approach to inform the design of novel short peptides with a potential antimicrobial activity.

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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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Rational Design of Alpha‐Helical Antimicrobial Peptides: Do's and Don'ts

Cited by 63 publications

References 35 publications

Latarcins: versatile spider venom peptides

Latarcins: versatile spider venom peptides

In Silico Structural Evaluation of Short Cationic Antimicrobial Peptides

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

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