Crabrolin, a natural antimicrobial peptide: structural properties

Aschi, Massimiliano; Bozzi, Argante; Luzi, Carla; Bouchemal, Nadia; Sette, Marco

doi:10.1002/psc.3013

Cited by 9 publications

(11 citation statements)

References 39 publications

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“…Molecular dynamics simulations are frequently used to provide information regarding (1) peptide conformation (e.g., % of helicity) [786][787][788][789][790][791][792][793][794][795][796][797][798], (2) peptide location (at the membrane interface or inserted into the bilayer core), and (3) orientation in the membrane [783,[787][788][789][790][792][793][794]796,[799][800][801][802][803][804][805][806]. As we stated previously, simulations can also provide information regarding the effects of the peptides on membrane properties, including (1) the extent of ordering in the acyl tails, (2) the overall membrane thickness, and (3) curvature [793,794,799,800,807] as well as the formation of membrane defects [794].…”

Section: A Clear Case Of Drug Membrane Interaction As Mechanism Of Action-antimicrobial Agentsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: A Clear Case Of Drug Membrane Interaction As Mechanism Of Action-antimicrobial Agentsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…Such mixture has been shown to favor the formation of secondary structure in other peptides. [34][35][36] Assignment of resonances was obtained by following the same strategy adopted for the peptide in water.…”

Section: Resultsmentioning

confidence: 99%

“…18 Even if the water/HFA mixture is not a system suitable for administration it is a good mimic of the membrane hydrophobic environment. [34][35][36] In this mixture, the data allowed defining the region of p28 able to organize in helical conformation. Interestingly, only a region of the peptide (residues 54-67) assumes a helical structure in the water/HFA solvent, suggesting that these residues have a high propensity to reach this final structure while the rest of the peptide shows a propensity to maintain a random conformation.…”

Section: Discussionmentioning

confidence: 99%

Solution structure of the anticancer p28 peptide in biomimetic medium

Cantini

Giannì

Savarin

et al. 2021

Journal of Peptide Science

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The p28 peptide derived from Pseudomonas aeruginosa azurin shows an anticancer activity after binding to p53 protein and is currently in Phase I of clinical trials. We have studied its structure in water and in a biomimetic media and show that the peptide is unstructured in water but when studied in a biomimetic medium assumes a structure very similar to the one observed in azurin, suggesting a high propensity of this peptide to maintain this secondary structure. Analysis of p28 sequences from different bacterial species indicates conservation of the secondary structure despite amino acid replacement in different positions, suggesting that others, similar peptides could be tested for binding to p53.

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“…To understand if such conformational preferences are maintained also in a less polar environment, as would be the case at the receptor binding site, the conformation of the peptides was also analyzed in solvent mixtures containing 0 to 100% hexafluoro-isopropanol (HFIP), at both pH values. It is well-known that the low polarity of the NaP/HFIP solutions promotes intra -peptide interactions over peptide-solvent interactions, and HFIP has been widely used to highlight secondary structure propensity in hydrophobic environments (Crescenzi et al, 2002 ; Tomaselli et al, 2006 ; Bernardi et al, 2010 ; Aschi et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Disordered Peptides Looking for Their Native Environment: Structural Basis of CB1 Endocannabinoid Receptor Binding to Pepcans

Emendato

Guerrini

Marzola

et al. 2018

Front. Mol. Biosci.

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Endocannabinoid peptides, or “pepcans,” are endogenous ligands of the CB1 cannabinoid receptor. Depending on their length, they display diverse activity: For instance, the nona-peptide Pepcan-9, also known as hemopressin, is a powerful inhibitor of CB1, whereas the longer variant Pepcan-12, which extends by only three amino acid residues at the N-terminus, acts on both CB1 and CB2 as an allosteric modulator, although with diverse effects. Despite active research on their pharmacological applications, very little is known about structure-activity relationships of pepcans. Different structures have been proposed for the nona-peptide, which has also been reported to form fibrillar aggregates. This might have affected the outcome and reproducibility of bioactivity studies. In an attempt of elucidating the determinants of both biological activity and aggregation propensity of Pepcan-9 and Pepcan-12, we have performed their structure characterization in solvent systems characterized by different polarity and pH. We have found that, while disordered in aqueous environment, both peptides display helical structure in less polar environment, mimicking the proteic receptor milieu. In the case of Pepcan-9, this structure is fully consistent with the observed modulation of the CB1. For Pepcan-12, whose allosteric binding site is still unknown, the presented structure is compatible with the binding at one of the previously proposed allosteric sites on CB1. These findings open the way to structure-driven design of selective peptide modulators of CB1.

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Crabrolin, a natural antimicrobial peptide: structural properties

Cited by 9 publications

References 39 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Solution structure of the anticancer p28 peptide in biomimetic medium

Disordered Peptides Looking for Their Native Environment: Structural Basis of CB1 Endocannabinoid Receptor Binding to Pepcans

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