3 research outputs found

    Development of PLGA Nanoparticles with a Glycosylated Myelin Oligodendrocyte Glycoprotein Epitope (MOG35-55) against Experimental Autoimmune Encephalomyelitis (EAE)

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    Multiple sclerosis (MS) is one of the most common neurodegenerative diseases in young adults, with early clinical symptoms seen in the central nervous system (CNS) myelin sheaths due to an attack caused by the patient's immune system. Activation of the immune system is mediated by the induction of an antigen-specific immune response involving the interaction of multiple T-cell types with antigen-presenting cells (APCs), such as dendritic cells (DCs). Antigen-specific therapeutic approaches focus on immune cells and autoantigens involved in the onset of disease symptoms, which are the main components of myelin proteins. The ability of such therapeutics to bind strongly to DCs could lead to immune system tolerance to the disease. Many modern approaches are based on peptide-based research, as, in recent years, they have been of particular interest in the development of new pharmaceuticals. The characteristics of peptides, such as short lifespan in the body and rapid hydrolysis, can be overcome by their entrapment in nanospheres, providing better pharmacokinetics and bioavailability. The present study describes the development of polymeric nanoparticles with encapsulated myelin peptide analogues involved in the development of MS, along with their biological evaluation as inhibitors of MS development and progression. In particular, particles of poly(lactic-co-glycolic) acid (PLGA) loaded with peptides based on mouse/rat (rMOG) epitope 35-55 of myelin oligodendrocyte glycoprotein (MOG) conjugated with saccharide residues were developed. More specifically, the MOG(35-55) peptide was conjugated with glucosamine to promote the interaction with mannose receptors (MRs) expressed by DCs. In addition, a study of slow release (dissolution) and quantification on both initially encapsulated peptide and daily release in saline in vitro was performed, followed by an evaluation of in vivo activity of the formulation on mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS, using both prophylactic and therapeutic protocols. Our results showed that the therapeutic protocol was effective in reducing EAE clinical scores and inflammation of the central nervous system and could be an alternative and promising approach against MS inducing tolerance against the disease

    A Cyclic Altered Peptide Analogue Based on Myelin Basic Protein 87โ€“99 Provides Lasting Prophylactic and Therapeutic Protection Against Acute Experimental Autoimmune Encephalomyelitis

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    In this report, amide-linked cyclic peptide analogues of the 87โ€“99 myelin basic protein (MBP) epitope, a candidate autoantigen in multiple sclerosis (MS), are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Cyclic altered peptide analogues of MBP87โ€“99 with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP72โ€“85-induced EAE in Lewis rats. The Lys91 and Pro96 of MBP87โ€“99 are crucial T-cell receptor (TCR) anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide)-MHC (major histocompability complex) for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS. The cyclic peptides were synthesized using Solid Phase Peptide Synthesis (SPPS) applied on the 9-fluorenylmethyloxycarboxyl/tert-butyl Fmoc/tBu methodology and combined with the 2-chlorotrityl chloride resin (CLTR-Cl). Cyclo(91โ€“99)[Ala96]MBP87โ€“99, cyclo(87โ€“99)[Ala91,96]MBP87โ€“99 and cyclo(87โ€“99)[Arg91, Ala96]MBP87โ€“99, but not wild-type linear MBP87โ€“99, strongly inhibited MBP72โ€“85-induced EAE in Lewis rats when administered using prophylactic and early therapeutic vaccination protocols. In particular, cyclo(87โ€“99)[Arg91, Ala96]MBP87โ€“99 was highly effective in preventing the onset and development of clinical symptoms and spinal cord pathology and providing lasting protection against EAE induction

    Influenza A M2 Spans the Membrane Bilayer, Perturbs its Organization and Differentiates the Effect of Amantadine and Spiro[pyrrolidine-2,2\u27-adamantane] AK13 on Lipids

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    The investigation and observations made for the M2TM, excess aminoadamantane ligands in DMPC were made using the simpler version of biophysical methods including SDC, SAXS and WAXS, MD simulations and ssNMR. 1H, 31P ssNMR and MD simulations, showed that M2TM in apo form or drug-bound form span the membrane interacting strongly with lipid acyl chain tails and the phosphate groups of the polar head surface. The MD simulations showed that the drugs anchor through their ammonium group with the lipid phosphate and occasionally with M2TM asparagine-44 carboxylate groups. The 13C ssNMR experiments allow the inspection of excess drug molecules and the assessment of its impact on the lipid head-group region. At low peptide concentrations of influenza A M2TM tetramer in DPMC bilayer, two lipid domains were observed that likely correspond to the M2TM boundary lipids and the bulk-like lipids. At high peptide concentrations, one domain was identified which constitute essentially all of the lipids which behave as boundary. This effect is likely due, according to the MD simulations, to the preference of AK13 to locate in closer vicinity to M2TM compared to Amt as well as the stronger ionic interactions of Amt primary ammonium group with phosphate groups, compared with the secondary buried ammonium group in AK13.<br /
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