Apport du fluor dans la synthèse et l'activité antipaludique de dérivés de l'artémisinine

PARIS-BIUP (751062107) / SudocSudocFranceF

Targeted delivery of compounds to Trypanosoma brucei using the melamine motif

There is an urgent need for the development of new drugs for the treatment of human African trypanosomiasis. The causative organism, Trypanosoma brucei, has been shown to have some unusual plasma membrane transporters, in particular the P2 aminopurine transporter and related permeases, which have been used for the selective targeting of trypanocidal compounds to the organism. In this paper, we report the addition of melamine-based P2-targeting motifs to three different classes of compound in order to try and improve activity through increased selective uptake. The classes reported here are fluoroquinolones, difluoromethylornithine and artesunate derivatives

Integrating solid-state NMR and computational modeling to investigate the structure and dynamics of membrane-associated ghrelin.

The peptide hormone ghrelin activates the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. This 28-residue peptide is acylated at Ser3 and is the only peptide hormone in the human body that is lipid-modified by an octanoyl group. Little is known about the structure and dynamics of membrane-associated ghrelin. We carried out solid-state NMR studies of ghrelin in lipid vesicles, followed by computational modeling of the peptide using Rosetta. Isotropic chemical shift data of isotopically labeled ghrelin provide information about the peptide's secondary structure. Spin diffusion experiments indicate that ghrelin binds to membranes via its lipidated Ser3. Further, Phe4, as well as electrostatics involving the peptide's positively charged residues and lipid polar headgroups, contribute to the binding energy. Other than the lipid anchor, ghrelin is highly flexible and mobile at the membrane surface. This observation is supported by our predicted model ensemble, which is in good agreement with experimentally determined chemical shifts. In the final ensemble of models, residues 8-17 form an α-helix, while residues 21-23 and 26-27 often adopt a polyproline II helical conformation. These helices appear to assist the peptide in forming an amphipathic conformation so that it can bind to the membrane

²H NMR spectra and order parameters of DMPC-<i>d</i>₅₄/DMPS membranes in the absence and presence of ghrelin and deacylghrelin.

<p>²H NMR spectra in DMPC-<i>d</i>₅₄/DMPS membranes (5/1, mol/mol) in the presence of ghrelin (A) and ghrelin-<i>d</i>₁₅ in DMPC/DMPS membranes (B). C) ²H NMR order parameters of DMPC-<i>d</i>₅₄/DMPS (5:1, mol/mol) membranes in the presence or absence of ghrelin or desacylghreliln (1:30 protein to lipid molar ratio) at a temperature of 30°C and a buffer content of 35 wt%. Error bars of the ²H NMR order parameters are smaller than the symbol size.</p

Outline of model ensemble selection algorithm.

<p>The flowchart outlines the process by which the agreement with experimental data is determined for an ensemble of models selected from a large pool.</p

Ghrelin sequence showing the isotopically labeled amino acids of the different ghrelin molecules and ssNMR spectra of membrane-embedded ghrelin.

<p>Labeled amino acids are shown in bold italics (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122444#pone.0122444.s010" target="_blank">S2 Table</a>). A) ¹³C CP MAS NMR spectrum of ghrelin (with Gly1, Leu5, and Ser6 ¹³C/¹⁵N labeled) in DMPC-<i>d</i>₆₇/DMPS-<i>d</i>₅₄ (5:1, mol/mol) membranes at a ghrelin concentration of 3.3 mol%. B) ¹H-¹³C MAS HetCor NMR spectrum of the same preparation, all at 30°C and a MAS frequency of 7 kHz.</p

Binding isotherms of ghrelin and desacyl ghrelin to DMPC/DMPG membranes.

<p>The amount of bound ghrelin (black squares) and desacyl ghrelin (red circles) as a function of lipid concentration is given. The binding data were fitted according to Eq. (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122444#pone.0122444.e001" target="_blank">1</a>).</p