Structure–function relationships in novel peptide dodecamers with broad-spectrum bactericidal and endotoxin-neutralizing activities

Mayo, Kevin H.; Haseman, Judith R.; Young, Helen C.; Mayo, Josef W.

doi:10.1042/bj3490717

Cited by 27 publications

(38 citation statements)

References 51 publications

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“…Each hydrogen bond identified was defined using two distance constraints: r NH-O = 1.8−2.5 Å and r N-O = 2.5−3.3 Å. The program X-PLOR [25] was used to calculate structures for anginex and βpep-28 using derived internuclear distance constraints as previously described [26]. Calculated structures were superimposed using the programs MolMol [27] and Insight II (Accelrys, Inc., San Diego, CA) and were analyzed using X-PLOR analysis routines.…”

Section: Structural Modelingmentioning

confidence: 99%

NMR solution structure of the angiostatic peptide anginex

Arroyo¹,

Mayo²

2007

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Anginex, a designed peptide 33mer, is known to function both as an antiangiogenic and bactericidal agent. Solving the NMR solution structure of the peptide is key to understand better its structureactivity relationships and to design more bioactive peptides and peptide mimetics. However, structure elucidation of anginex has been elusive due to subunit exchange-induced resonance broadening. Here, we found that performing NMR structural studies in a micellar environment abolishes exchange broadening and allows the structure of anginex to be determined. Anginex folds in an amphipathic, three-stranded antiparallel β-sheet conformation with functionally key hydrophobic residues lying on one face of the β-sheet and positively charged, mostly lysine residues, lying on the opposite face. Structural comparison is made with a homologous, yet relatively inactive peptide, βpep-28. These results contribute to the design of peptidomimetics of anginex for therapeutic use against angiogenically-related diseases like cancer, as well as infectious diseases.

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Section: Structural Modelingmentioning

confidence: 99%

NMR solution structure of the angiostatic peptide anginex

Arroyo¹,

Mayo²

2007

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…Other examples of such peptides are the cecropins,15 magainins,16 proline-arginine-rich peptides,17 sapecin, 18 tachyplesin,19 the defensins,20,21βpep peptides,22,23 and dodecapeptide SC4. 24 More recently, a lactoferrin-based peptide, LF11,25 and an N-acylated form lauryl-LF1126 have been identified. The structures of many of these peptides are known and range from turn/ loop to helix to β-sheet.…”

Section: Introductionmentioning

confidence: 99%

Topomimetics of Amphipathic β-Sheet and Helix-Forming Bactericidal Peptides Neutralize Lipopolysaccharide Endotoxins

et al. 2006

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Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and β-sheet-forming βpep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10 −8 M range, making them as effective as bactericidal/permeability increasing (BPI) protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.

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“…This may have been attributable to the extremely labile ester-linked acyl moieties in dioleoyl-substituted spermine. Indeed, recent reports indicate that, both in lipoamines with stable, amide-linked acyl groups (65) as well as in cationic amphipathic peptides (28,46), a correlation between antiendotoxic and antibacterial activity does exist. Therapeutic agents with combined antibacterial and endotoxin-sequestering activities may offer significant advantages in addressing the problem of antibiotic-induced endotoxin release (22)(23)(24), a contributory factor in the development of endotoxic shock in gram-negative sepsis (38,39).…”

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confidence: 99%

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

Balakrishna

Wood

Nguyen

et al. 2006

Antimicrob Agents Chemother

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A homologous series of mono-and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gramnegative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C 8 or C 9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.The accelerated emergence of many strains of multidrugresistant bacteria as a result of widespread use and misuse of antibiotics has mandated the urgent need for a renewed search for novel antibacterial agents. The presence of an outer membrane (OM) in gram-negative bacteria provides an effective protective barrier in these organisms (33, 34) to antimicrobial agents that may otherwise be active. For instance, it has been reported that in antibiotics of natural origin that are active against gram-positive bacteria, more than 90% lacked activity at a useful level against Escherichia coli (55). The barrier, formed by a divalent cation-cross-linked matrix (36, 40) of lipopolysaccharide (LPS) molecules on the outer leaflet of the OM (17, 48), can be breached by metal-chelating agents such as EDTA or via displacement of LPS-bound metals by polycations of diverse structural classes (20,36,40,54,57).Polymyxin B (PMB), a cyclic, pentacationic, amphipathic peptide antibiotic isolated from Bacillus polymyxa (49) is a prototype membrane-perturbing agent whose antibacterial action is manifested via its binding to the lipid A moiety of LPS. Perturbation of the OM alone has been thought to result in bacterial killing, since immobilized PMB can disrupt the OM (41); however, alternate hypotheses concerning "self-promoted" uptake of the antibiotic and subsequent perturbation of the inner membrane (IM), culminating in bacterial lysis, have also been suggested (11, 64). The recognition that membrane-active antimicrobials have not yet been exploited adequately in the clinic has spurred the search for noncytolytic, selective bacterial membrane-permeabilizing agents, notable examples of which include cationic peptides (18,19) and smallmolecule PMB mimics (12,13,27,44). The use of cationic peptides as...

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Structure–function relationships in novel peptide dodecamers with broad-spectrum bactericidal and endotoxin-neutralizing activities

Cited by 27 publications

References 51 publications

NMR solution structure of the angiostatic peptide anginex

NMR solution structure of the angiostatic peptide anginex

Topomimetics of Amphipathic β-Sheet and Helix-Forming Bactericidal Peptides Neutralize Lipopolysaccharide Endotoxins

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

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