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Structural and mechanistic studies of bioactive peptidesPukala, Tara Louise January 2006 (has links)
Venoms, toxins and host-defence systems constitute rich sources of biologically active molecules, many of which have enormous therapeutic and biotechnological potential. In particular, peptides are often a significant component of these chemical arsenals, and are fundamentally important as biological effector molecules. The research presented in this thesis is centred on the isolation and investigation of peptides from both frogs and spiders, and endeavours to probe the important structural and mechanistic features of these bioactive compounds. The skin peptide profiles of interspecific hybrids between the green tree frog Litoria caerulea and the magnificent tree frog Litoria splendida have been investigated in a ninemonth survey. Fourteen peptides were characterised primarily using mass spectrometry, of which three had not been identified previously in the skin secretions of either parent. A number of these peptides are antibacterial agents, while others effectively inhibit the formation of nitric oxide by neuronal nitric oxide synthase. Implications for the genetics and expression of amphibian dermal peptides are also discussed. The majority of frogs of the genus Litoria contain at least one peptide in their glandular secretion capable of inhibiting the formation of nitric oxide by the enzyme neuronal nitric oxide synthase. This was proposed to occur by preventing the association of the regulatory cofactor, Ca²⁺ -calmodulin, with its binding site on the enzyme. Non-covalent binding of the amphibian peptides to calmodulin in the presence of Ca²⁺ has been confirmed using electrospray ionisation mass spectrometry, by the observation of complexes in the gas phase with a 1 : 1 : 4 calmodulin / peptide / Ca²⁺ stoichiometry. In addition, the structure and binding interactions of caerin 1.8, a potent nitric oxide synthase inhibitor, have been further probed using mass spectrometry and nuclear magnetic resonance spectroscopy techniques. Recently a number of small, disulfide - containing neuropeptides of the signiferin and riparin families have been characterised from the skin secretion of frogs of the Crinia genus. Of these, signiferin 1 and riparin 1.1 are both ten residue peptides with similar primary sequences, however appear to have a significantly different spectrum of bioactivity. Although both act at cholecystokinin-2 receptors, signiferin 1 is smooth muscle active while riparin 1.1 is not, and instead causes proliferation of lymphocytes. The three-dimensional structures of these peptides were determined using nuclear magnetic resonance spectroscopy and restrained molecular dynamics calculations. Both signiferin 1 and riparin 1.1 adopt β - turn type conformations, however differences in these structures may be responsible for the variation in biological activity noted for these peptides. The dermal secretions of most Australian frogs contain at least one broad-spectrum peptide antibiotic, and often a series of peptides with differing activity to afford greater protection against microbial pathogens. Solid state nuclear magnetic resonance spectroscopy studies were carried out to investigate the interaction of a number of these antibacterial peptides with anionic model membranes, and the results are compared with work previously reported using neutral lipids. It appears the peptides may have a different mode of interaction with the membranes depending upon the charge of the lipid head group. The cupiennin 1 peptides have been identified in the venom of the neotropical wandering spider, Cupiennius salei, and demonstrate potent wide-spectrum antibacterial activity. Primary sequence analysis of these peptides suggests a unique amphipathic structure distinctly different from that of other potentially helical cationic antimicrobial peptides isolated thus far. Using nuclear magnetic resonance spectroscopy and restrained molecular dynamics calculations, cupiennin 1a was found to adopt an α- helical structure with a flexible central hinge region in membrane mimicking solvents. Following this, nuclear magnetic resonance spectroscopy methods were used to further probe the antibacterial and the newly identified neuronal nitric oxide synthase inhibitory activity of this peptide. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, Discipline of Chemistry, 2006
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Chemistry and medical implications of novel amphibian peptides : a thesis submitted for the degree of Doctor of Philosophy / by Paul Andrew Wabnitz.Wabnitz, Paul Andrew January 1999 (has links)
Copies of author's previously published articles inserted. / Includes bibliographical references. / xv, 210 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / A chemical and pharmacological investigation of compounds derived from amphibian skin. Isolates novel amphibian peptides and further investigates the biological activity of some of the peptides discovered. / Thesis (Ph.D.)--University of Adelaide, Dept. of Chemistry, 2000
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Study of Cell Penetrating Peptide Uptake and Cancer Cell Discrimination with Raman Spectroscopy and MicroscopyUnknown Date (has links)
Cell penetrating peptides (CPPs) are short sequences of amino acids that excel in
crossing the cellular membrane without inducing cytotoxicity Interest in these peptides
stem from their ability to be attached, and grant their penetrating properties to, a variety
of cargo In this work we have combined the application of Confocal Raman Microscopy
(CRM) and Atomic Force Microscopy for the first time to examine the interactions of
unlabeled Transportan (TP), one of the most well studied CPPs, with mammalian cells
CRM’s capability to discriminate control and treated cell groups was verified by principal
component analysis (PCA) and linear discriminant analysis (LDA) and was 93-100%
accurate We’ve determined that at a concentration of 20 μM TP enters cells through a
non-endocytotic mechanism, has a high affinity for the cytoplasm and membranes, and
results in a significant increase in cellular stiffness Our work provides the first direct
evidence of this cell-stiffening phenomenon SFTI-1, the smallest member of a bicyclic, cysteine rich class of CPPs, was
examined by CRM to determine the potential role of cyclic structure on cellular uptake
The peptide, along with monocyclic and linear analogs was heavy isotope labeled and
incubated with mammalian cells at numerous concentrations and timespans Our work is
the first SFTI-1 uptake study forgoing the use of fluorophore conjugates, which have
been linked to artificial cellular uptake We demonstrate herein the absence of any CRM
detectable uptake, providing the first evidence that SFTI-1 may not be a CPP
Finally, CRM was applied to the discrimination of normal and basal cell
carcinoma cells obtained from the same donor The use of patient matched cells avoids
the normal biochemical variations that exist among individuals, ensuring that
discrimination is based solely on the cell’s diseased state CRM spectra, analyzed by
PCA and LDA, were capable of spectral discrimination with 100% accuracy Major
differences in the cancerous cells were an increase in lipids and nucleic acids, and an
overall decrease in protein We also demonstrate an enhancement in Raman signal
through the use of an aluminum foil substrate, providing a practical approach for
measuring cells with thin morphologies / Includes bibliography / Dissertation (PhD)--Florida Atlantic University, 2016 / FAU Electronic Theses and Dissertations Collection
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Cyclic lipodepsipeptides as lead structures for the discovery of new antiobioticsUnknown Date (has links)
With antimicrobial resistance to current drugs steadily rising, the development of new antibiotics with novel mechanisms of action has become an imperative. The majority of life-threatening infections worldwide are caused by "ESKAPE" pathogens which are encountered in more than 40% of hospital-acquired infections, and are resistant to the majority of commonly used antibiotics. Naturally occurring cyclic depsipeptides, microbial secondary metabolites that contain one or more ester bonds in addition to amide bonds, have emerged as an important source of pharmacologically active compounds or lead structures for the development of novel antibiotics. Some of those peptides are either already marketed (daptomycin) or in advanced stages of clinical development (ramoplanin). Structurally simple, yet potent, fusaricidin/LI-F and lysobactin families of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents capable of overco ming infections caused by multidrug-resistant bacteria. These natural products exhibit potent antimicrobial activity against a variety of clinically relevant fungi and Gram-positive bacteria. Therefore, access to these classes of natural products and their synthetic analogs, combined with elucidation of their mode of action represent important initial steps toward full exploitation of their antmicrobial potential. This dissertation describes a general approach toward the solid-phase synthesis of fusaricidin/LI-F and lysobactin analogs and an extensive structure-activity relationship (SAR) study. We have devised a simple and robust preparation strategy based on standard Fmoc solid-phase peptide synthesis protocols. / The SAR study revealed key structural requirements for fusaricidin/LI-F and related cyclic lipopeptides antibacterial activity, including the presence of the guanidino moietly at the end of the lipidic tail, hydrophobic amino acid residues, and peptide conformation Moreover, substitution of the ester bond with an amide bond significantly improved stability under physiologically relevant conditions and reduced toxicity. In addition, we have shown that these antibacterial peptides exert their mode of action via a novel mechanism, which invloves bacterial membrane interactions, followed by peptide internalization. Altogether, the research described in this dissertation demonstrates that new antibiotics derived from fusaricidin/LI-F natural products, have the potential to meet the challenge of antibiotic resistance in Gram-positive bacteria. / by Nina Bionda. / Thesis (Ph.D.)--Florida Atlantic University, 2013. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.
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Morphological and neurological outcome in the short time study after spinal cord injury in miceKazemi, Soheila 17 September 2012 (has links)
Spinal cord injury (SCI) is a devastating disease which poses health problems in human and veterinary medicine. SCI causes neurological disability, with loss of motor, sensory and autonomic function. This study investigated the efficacy of local treatment with IKVAV-peptide on spinal cord regeneration following compression injury at T12 vertebra in Balb-c mice. IKVAV-peptide is a membrane spanning peptide known to have a long half-life and the peptide motif IKVAV. Thirty Blab-c female mice were used. Hemilaminectomy was performed at T12 and spinal cords were compressed using extradural application of a 24 g modified aneurysm clip for 1 min in the treatment groups. After 24 hours mice were treated with one of 4 different treatments including isoleucine-lysine-valine-alanine-valaine(IKVAV), IKVAVpeptide, peptide and mannitol (vehicle). Functional improvement was assessed every day using Basso, Beattie, Bresnahan (BBB) Locomotor Rating Scale. 28 days later, the mice were euthanized, and spinal cord segments were studied histologically. Statistical analysis, one-way and two-way analysis of variance (ANOVA) and linear regression model were used to measure some parameters and describe the outcome
after SCI. Over a 4weeks period, IKVAV-peptide group demonstrated statistical and histological evidence of cellular reconstruction and behavioral improvement. The BBB score in the IKVAV-peptide group increased by 5.4 (25%) points, the IKVAV and peptide groups by approximately 1 point (5%) and the mannitol group by 4 points (19%). The number of protoplasmic astrocytes in the IKVAV-peptide group was significantly increased compared to IKVAV, mannitol and normal groups but not with the peptide group (p<0.001). Neuron and muscle bundle size were also increased significantly (p<0.05 and p<0.007, resp.) in the IKVAV-peptide group compared to other treatment groups. The treated control groups showed cellular and gross damages including neuron inactivation and muscle atrophy, gliosis and inability of movement. / Graduation date: 2013
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Effects of coadministration of D-Napvsipq [NAP] and D-Sallrsipa [SAL] on spatial learning after developmental alcohol exposureWagner, Jennifer Lynne January 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Despite warnings about the dangers of drinking during pregnancy, little progress has been made in reducing alcohol drinking among women of childbearing age. Even after the recognition of pregnancy, 15% of women continue to drink, 3% of which admit to binge drinking. Because we cannot stop women from drinking during pregnancy, and many children with fetal alcohol spectrum disorders (FASD) are adopted, there is a significant need to develop postnatal interventions that can improve the long-term outcome of children adversely affected by prenatal alcohol exposure. This thesis aims to evaluate one promising new treatment in the rehabilitation or rescue of specific learning deficits long after the damage has occurred.
The treatment evaluated herein (40µg D-NAP + 40µg D-SAL) has long been used in the prevention of the detrimental effects of long-term and binge-like alcohol exposures in rodent models of fetal alcohol syndrome and FASD. Until recently this peptide treatment had only been shown to be effective in preventing some of the consequences of alcohol exposure when administered concurrently with the prenatal alcohol exposure. A recent report by Incerti and colleagues (2010c), however, reported that these peptides could completely reverse a profound spatial learning deficit induced by one episode of a heavy binge-like alcohol exposure (5.9g.kg in a single intraperitoneal injection) on gestational day 8 (G8) in C57BL/6 mice. In that report, the peptide treatment was administered starting in late adolescence, beginning three days prior to and throughout water maze training, and the profound deficits in their alcohol-placebo group were completely eliminated in the alcohol-peptide group. There are currently no FDA-approved treatments for FASD. An effective treatment for the cognitive and behavioral dysfunctions suffered by the 1% of people born today could potentially improve the lives of millions of children and adults.
The first aim of this thesis was to determine whether the peptide treatment could reverse the significant spatial learning deficits we have demonstrated in adult C57BL/6 mice given high-dose binge-like alcohol exposure (2.5 g/kg in each of two intraperitoneal injections separated by two hours) on postnatal day (P)7. When administered three days prior to and throughout water maze testing (P67-76), the peptide treatment had no effect on spatial learning.
The second aim sought to determine whether the same peptide treatment could reverse water maze spatial learning deficits in G8 binge-like exposure models, as reported by Incerti et al. (2010c). For this analysis, the first study used a different binge-like alcohol exposure model that is more commonly used than that employed by the Incerti et al. (2010c) study, namely administration of 2.8g/kg in each of two intraperitoneal injections separated by four hours (Sulik et al., 1981). This model has been shown to produce high peak blood alcohol concentrations and neuroanatomical aberrations in the hippocampal formation and septal regions (Parnell et al., 2009), which have been implicated in learning and memory. Surprisingly, this G8 binge-like alcohol exposure failed to produce a spatial learning deficit, undermining the usefulness of this model in evaluating the peptide effects. In direct contrast to the outcomes of Incerti et al. (2010c), the G8 Webster alcohol exposure was also unable to produce any deficits in acquisition of spatial learning in the Morris water maze.
Surprisingly, neither of the heavy binge-like alcohol exposures on G8 were able to produce spatial learning deficits in the Morris water maze. The binge-like alcohol exposure on P7 did yield the expected spatial learning deficit, but the peptide treatment was unsuccessful in recovering water maze learning. These findings fail to support oral administration of 40µg D-NAP and 40 µg D-SAL as a potential therapy for postnatal alcohol-induced spatial learning deficits in adult mice.
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