Interactions of a designed peptide with lipopolysaccharide: Bound conformation and anti-endotoxic activity

Bhunia, Anirban; Chua, Geok Lin; Domadia, Prerna N.; Warshakoon, Hemamali J.; Cromer, Jens R.; David, Sunil A.; Bhattacharjya, Surajit

doi:10.1016/j.bbrc.2008.02.105

Cited by 21 publications

(23 citation statements)

References 20 publications

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“…The comparison of the results with those obtained for a biologically inactive precursor-type analogue with four shorter acyl chains, demonstrated the key importance of hydrophobic interactions for maintaining the conformation of such molecules. [130] The conformation of the isolated peptide was highly flexible, but underwent a striking stabilization in the presence of LPS. This fact could be responsible for the lack of both endotoxic and antagonistic activities, due to the expected large entropic penalty that would arise upon binding to the LPS receptors.…”

Section: Reviewmentioning

confidence: 99%

Chemistry of Lipid A: At the Heart of Innate Immunity

Molinaro

Holst

Lorenzo

et al. 2014

Chemistry A European J

205

185

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In many Gram-negative bacteria, lipopolysaccharide (LPS) and its lipid A moiety are pivotal for bacterial survival. Depending on its structure, lipid A carries the toxic properties of the LPS and acts as a potent elicitor of the host innate immune system via the Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) receptor complex. It often causes a wide variety of biological effects ranging from a remarkable enhancement of the resistance to the infection to an uncontrolled and massive immune response resulting in sepsis and septic shock. Since the bioactivity of lipid A is strongly influenced by its primary structure, a broad range of chemical syntheses of lipid A derivatives have made an enormous contribution to the characterization of lipid A bioactivity, providing novel pharmacological targets for the development of new biomedical therapies. Here, we describe and discuss the chemical aspects regarding lipid A and its role in innate immunity, from the (bio)synthesis, isolation and characterization to the molecular recognition at the atomic level.

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Section: Reviewmentioning

confidence: 99%

Chemistry of Lipid A: At the Heart of Innate Immunity

Molinaro

Holst

Lorenzo

et al. 2014

Chemistry A European J

205

185

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“…As described above, a variety of cationic, amphipathic peptides share these properties, as was evident with melittin, a basic, amphipathic peptide constituent of bee venom [37]. as well as structurally unrelated peptides such as gramicidin S, tyrocidin, efrapeptin as well as de novo designed peptides [38],[39],[40]. Hypothesizing that polycationicity and amphipathicity are necessary and sufficient requirements for bacterial membrane perturbation and for LPS sequestration, we turned our attention to small molecules embodying the above-mentioned physical properties.…”

Section: Neutralization Of Endotoxin By Lipopolyaminesmentioning

confidence: 99%

Bacterial Cell Wall Compounds as Promising Targets of Antimicrobial Agents I. Antimicrobial Peptides and Lipopolyamines

Tejada¹,

Sánchez-Gómez²,

Rázquin-Olazarán³

et al. 2012

CDT

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The first barrier that an antimicrobial agent must overcome when interacting with its target is the microbial cell wall. In the case of Gram-negative bacteria, additional to the cytoplasmic membrane and the peptidoglycan layer, an outer membrane (OM) is the outermost barrier. The OM has an asymmetric distribution of the lipids with phospholipids and lipopolysaccharide (LPS) located in the inner and outer leaflets, respectively. In contrast, Gram-positive bacteria lack OM and possess a much thicker peptidoglycan layer compared to their Gram-negative counterparts. An additional class of amphiphiles exist in Gram-positives, the lipoteichoic acids (LTA), which may represent important structural components. These long molecules cross-bridge the entire cell envelope with their lipid component inserting into the outer leaflet of the cytoplasmic membrane and the teichoic acid portion penetrating into the peptidoglycan layer. Furthermore, both classes of bacteria have other important amphiphiles, such as lipoproteins, whose importance has become evident only recently. It is not known yet whether any of these amphiphilic components are able to stimulate the immune system under physiological conditions as constituents of intact bacteria. However, all of them have a very high pro-inflammatory activity when released from the cell. Such a release may take place through the interaction with the immune system, or with antibiotics (particularly with those targeting cell wall components), or simply by the bacterial division. Therefore, a given antimicrobial agent must ideally have a double character, namely, it must overcome the bacterial cell wall barrier, without inducing the liberation of the pro-inflammatory amphiphiles. Here, new data are presented which describe the development and use of membrane-active antimicrobial agents, in particular antimicrobial peptides (AMPs) and lipopolyamines. In this way, essential progress was achieved, in particular with respect to the inhibition of deleterious consequences of bacterial infections such as severe sepsis and septic shock.

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“…The upward position of the ITC titration peaks (Figure S3 B) and the resultant positive integrated heats indicate that the association between QF8 and LPS is an endothermic process. [34] With a single site independent binding model, the enthalpy (DH) of association between QF8 peptide and LPS is 7.8 kcal mol À1 with an equilibrium association constant QF8/LPS (due to heterogeneity of LPS) obtained at pH 7.4. This ratio likely corresponds to the net charge compensation between anionic LPS (2-4 negative charges) and cationic QF8 (seven positive charges).…”

Section: Isothermal Titration Calorimetry (Itc)mentioning

confidence: 99%

“…All measurements were done in triplicate. www.chembiochem.org ITC measurements: [34] LPS was dissolved in PBS, pH 7.4, to give a 75 mm solution (assumed M W = 10 000 kDa) equilibrated by dialysis, overnight, and degassed under vacuum. The QF8 peptide was dissolved in the same buffer at 1 mm and degassed under vacuum.…”

mentioning

confidence: 99%

Bacterial Glycoprofiling by Using Random Sequence Peptide Microarrays

et al. 2009

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Current analytical methods have been slow in addressing the growing need for glyco-analysis. A new generation of more empirical high-throughput (HTP) tools is needed to aid the advance of this important field. To this end, we have developed a new HTP screening platform for identification of surface-immobilized peptides that specifically bind O-antigenic glycans of bacterial lipopolysaccharides (LPS). This method involves screening of random sequence peptide libraries in addressable high-density microarray format with the newly developed luminescent LPS-quantum dot micelles. Screening of LPS fractions from O111:B4 and O55:B5 serotypes of E. coli on a microarray consisting of 10,000 20-mer peptide features revealed minor differences, while comparison of LPS from E. coli O111:B4 and P. aeruginosa produced sets of highly specific peptides. Peptides strongly binding to the E. coli LPS were highly enriched in aromatic and cationic amino acids, and most of these inhibited growth of E. coli. Flow cytometry and isothermal titration calorimetry (ITC) experiments showed that some of these peptides bind LPS in-solution with a K(d) of 1.75 microM. Peptide selections against P. aeruginosa were largely composed of hydrogen-bond forming amino acids in accordance with dramatic compositional differences in O-antigenic glycans in E. coli and P. aeruginosa. While the main value of this approach lies in the ability to rapidly differentiate bacterial and possibly other complex glycans, the peptides discovered here can potentially be used off-array as antiendotoxic and antimicrobial lead compounds, and on-array/on-bead as diagnostic and affinity reagents.

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Interactions of a designed peptide with lipopolysaccharide: Bound conformation and anti-endotoxic activity

Cited by 21 publications

References 20 publications

Chemistry of Lipid A: At the Heart of Innate Immunity

Chemistry of Lipid A: At the Heart of Innate Immunity

Bacterial Cell Wall Compounds as Promising Targets of Antimicrobial Agents I. Antimicrobial Peptides and Lipopolyamines

Bacterial Glycoprofiling by Using Random Sequence Peptide Microarrays

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