Marie-Isabel Aguilar

Bio: Marie-Isabel Aguilar is an academic researcher from Monash University, Clayton campus. The author has contributed to research in topics: Peptide & High-performance liquid chromatography. The author has an hindex of 48, co-authored 236 publications receiving 7151 citations. Previous affiliations of Marie-Isabel Aguilar include Monash University & University of Melbourne.

β-amino acids: Versatile peptidomimetics

Abstract: The use of peptidomimetics has emerged as a powerful means for overcoming the limitations inherent in the physical characteristics of peptides thus improving their therapeutic potential. A peptidomimetic approach that has emerged in recent years with significant potential, is the use of β-amino acids. β-Amino acids are similar to α-amino acids in that they contain an amino terminus and a carboxyl terminus. However, in β-amino acids two carbon atoms separate these functional termini. β-amino acids, with a specific side chain, can exist as the R or S isomers at either the α (C2) carbon or the β (C3) carbon. This results in a total of 4 possible diastereoisomers for any given side chain. The flexibility to generate a vast range of stereo- and regioisomers, together with the possibility of disubstitution, significantly expands the structural diversity of β-amino acids thereby providing enormous scope for molecular design. The incorporation of β-amino acids has been successful in creating peptidomimetics that not only have potent biological activity, but are also resistant to proteolysis. This article reviews the rapidly expanding applications of β-amino acids in the design of bioactive peptide analogues ranging from receptor agonists and antagonists, MHC-binding peptides, antimicrobial peptides and peptidase inhibitors. Given their structural diversity taken together with the ease of synthesis and incorporation into peptide sequences using standard solid-phase peptide synthesis techniques, β-amino acids have the potential to form a new platform technology for peptidomimetic design and synthesis.

Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors

Abstract: AT1R (angiotensin type 1 receptor) and AT2R (angiotensin type 2 receptor) are well known to be involved in the complex cardiovascular actions of AngII (angiotensin II) However, shorter peptide fragments of AngII are thought to have biological activity in their own right and elicit effects that oppose those mediated by AngII In the present study, we have used HEK (human embryonic kidney)-293 cells stably transfected with either AT1R or AT2R to perform a systematic analysis of binding affinities of all the major angiotensin peptides Additionally, we tested the novel AT2R agonist Compound 21, as well as the MasR (Mas receptor) agonist and antagonist AVE0991 and A-779 respectively, for their ability to bind to AT1R or AT2R Candesartan, CGP42214 and PD123319 were used as reference compounds Binding studies using 125I-[Sar1Ile8]AngII on the AT1R-transfected HEK-293 cells revealed only AngII, AngIII [angiotensin III; angiotensin-(2-8)] and candesartan to have high affinity for AT1R In the AT2R-transfected HEK-293 cells, competition for 125I-[Sar1Ile8]AngII binding was observed for all ligands except candesartan, AVE0991 and A-779, the latter two compounds having negligible affinity at either AT1R or AT2R The rank order of affinity of ligands at AT2R was CGP42112>AngII≥AngIII>Compound 21≥PD123319≫AngIV [angiotensin IV; angiotensin-(3-8)]>Ang-(1-7) [angiotensin-(1-7)] Of note, although AngIV and Ang-(1-7) exhibited only modest affinity at AT2R compared with AngII, these two angiotensin peptides, together with AngIII, had substantial AT2R selectivity over AT1R Collectively, our results suggest that shorter angiotensin peptides can act as endogenous ligands at AT2R

The β-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism

Abstract: Neuritic abnormalities are a major hallmark of Alzheimer's disease (AD) pathology. Accumulation of β-amyloid protein (Aβ) in the brain causes changes in neuritic processes in individuals with this disease. In this study, we show that Aβ decreases neurite outgrowth from SH-SY5Y human neuroblastoma cells. To explore molecular pathways by which Aβ alters neurite outgrowth, we examined the activation and localization of RhoA and Rac1 which regulate the level and phosphorylation of the collapsin response mediator protein-2 (CRMP-2). Aβ increased the levels of the GTP-bound (active) form of RhoA in SH-SY5Y cells. This increase in GTP-RhoA correlated with an increase in an alternatively spliced form of CRMP-2 (CRMP-2A) and its threonine phosphorylated form. Both a constitutively active form of Rac1 (CA-Rac1) and the Rho kinase inhibitor, Y27632, decreased levels of the CRMP-2A variant and decreased threonine phosphorylation caused by Aβ stimulation. The amount of tubulin bound to CRMP-2 was decreased in the presence of Aβ but Y27632 increased the levels of tubulin bound to CRMP-2. Increased levels of both RhoA and CRMP-2 were found in neurons surrounding amyloid plaques in the cerebral cortex of the APP(Swe) Tg2576 mice. We found that there was an increase in threonine phosphorylation of CRMP-2 in Tg2576 mice and the increase correlated with a decrease in the ability of CRMP-2 to bind tubulin. The results suggest that Aβ-induced neurite outgrowth inhibition may be initiated through a mechanism in which Aβ causes an increase in Rho GTPase activity which, in turn, phosphorylates CRMP-2 to interfere with tubulin assembly in neurites.

Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of neurodegeneration.

Abstract: Familial amyloidotic polyneuropathy (FAP) is an inherited autosomal dominant disease that is commonly caused by accumulation of deposits of transthyretin (TTR) amyloid around peripheral nerves. The only effective treatment for FAP is liver transplantation. However, recent studies on TTR aggregation provide clues to the mechanism of the molecular pathogenesis of FAP and suggest new avenues for therapeutic intervention. It is increasingly recognized that there are common features of a number of protein-misfolding diseases that can lead to neurodegeneration. As for other amyloidogenic proteins, the most toxic forms of aggregated TTR are likely to be the low-molecular-mass diffusible species, and there is increasing evidence that this toxicity is mediated by disturbances in calcium homeostasis. This article reviews what is already known about the mechanism of TTR aggregation in FAP and describes how recent discoveries in other areas of amyloid research, particularly Alzheimer's disease, provide clues to the molecular pathogenesis of FAP.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

Mechanisms of Antimicrobial Peptide Action and Resistance

Abstract: Antimicrobial peptides have been isolated and characterized from tissues and organisms representing virtually every kingdom and phylum, ranging from prokaryotes to humans. Yet, recurrent structural and functional themes in mechanisms of action and resistance are observed among peptides of widely diverse source and composition. Biochemical distinctions among the peptides themselves, target versus host cells, and the microenvironments in which these counterparts convene, likely provide for varying degrees of selective toxicity among diverse antimicrobial peptide types. Moreover, many antimicrobial peptides employ sophisticated and dynamic mechanisms of action to effect rapid and potent activities consistent with their likely roles in antimicrobial host defense. In balance, successful microbial pathogens have evolved multifaceted and effective countermeasures to avoid exposure to and subvert mechanisms of antimicrobial peptides. A clearer recognition of these opposing themes will significantly advance our understanding of how antimicrobial peptides function in defense against infection. Furthermore, this understanding may provide new models and strategies for developing novel antimicrobial agents, that may also augment immunity, restore potency or amplify the mechanisms of conventional antibiotics, and minimize antimicrobial resistance mechanisms among pathogens. From these perspectives, the intention of this review is to illustrate the contemporary structural and functional themes among mechanisms of antimicrobial peptide action and resistance.

Designing antimicrobial peptides: form follows function

Abstract: Multidrug-resistant bacteria are a severe threat to public health. Conventional antibiotics are becoming increasingly ineffective as a result of resistance, and it is imperative to find new antibacterial strategies. Natural antimicrobials, known as host defence peptides or antimicrobial peptides, defend host organisms against microbes but most have modest direct antibiotic activity. Enhanced variants have been developed using straightforward design and optimization strategies and are being tested clinically. Here, we describe advanced computer-assisted design strategies that address the difficult problem of relating primary sequence to peptide structure, and are delivering more potent, cost-effective, broad-spectrum peptides as potential next-generation antibiotics.

Surface plasmon resonance in gold nanoparticles: a review.

Abstract: In the last two decades, plasmon resonance in gold nanoparticles (Au NPs) has been the subject of intense research efforts. Plasmon physics is intriguing and its precise modelling proved to be challenging. In fact, plasmons are highly responsive to a multitude of factors, either intrinsic to the Au NPs or from the environment, and recently the need emerged for the correction of standard electromagnetic approaches with quantum effects. Applications related to plasmon absorption and scattering in Au NPs are impressively numerous, ranging from sensing to photothermal effects to cell imaging. Also, plasmon-enhanced phenomena are highly interesting for multiple purposes, including, for instance, Raman spectroscopy of nearby analytes, catalysis, or sunlight energy conversion. In addition, plasmon excitation is involved in a series of advanced physical processes such as non-linear optics, optical trapping, magneto-plasmonics, and optical activity. Here, we provide the general overview of the field and the background for appropriate modelling of the physical phenomena. Then, we report on the current state of the art and most recent applications of plasmon resonance in Au NPs.