Les récepteurs Tyrosine kinases de Schistosoma mansoni : à la recherche de nouvelles cibles thérapeutiques

Malgré les efforts entrepris pour contrôler sa transmission, la schistosomose reste la seconde endémie parasitaire mondiale et représente toujours un véritable problème de santé publique ainsi qu’un handicap pour la croissance économique de bon nombre de pays en voie de développement. Dans le cas de l’infection à Schistosoma mansoni, l’apparition de cas de résistance au praziquantel, drogue de choix actuelle pour le traitement de la maladie, représente une menace importante pour la santé des populations et motive la poursuite de recherches visant à la découverte de nouvelles molécules. Les récents succès obtenus en chimiothérapie anticancéreuse avec l’utilisation d’inhibiteurs spécifiques de récepteurs tyrosine kinases (RTK), tel que le récepteur EGF, nous ont conduits à considérer que, d’une manière analogue, les récepteurs aux facteurs de croissance du parasite pourraient être des cibles thérapeutiques potentielles. Trois RTK ont été identifiés chez S. mansoni : un récepteur de l’EGF, un récepteur de l’insuline et un récepteur complètement original appartenant probablement à une classe de RTK qui n’avait pas été encore identifiée. Les études structurales et fonctionnelles ont démontré la conservation et les divergences de ces RTK parasitaires et en font des candidats privilégiés en tant que nouvelles cibles chimiothérapeutiques

Comment on « N-terminal Protein Tail Acts as Aggregation Protective Entropic Bristles : The SUMO Case »

We provide a robust protocol for the far-UV CD analysis of SUMO-2 protein and SUMO-2 core domain as well as all the data as supplementary files for those interested by the study of SUMO protein conformation.These analyses were performed after having read the report published in 2014 by Grana-Montes, R. et al. (Grana-Montes, R.; Marinelli, P.; Reverter, D.; Ventura, S., N-terminal protein tails act as aggregation protective entropic bristles: the SUMO case. Biomacromolecules 2014, 15 (4), 1194-203. DOI: 10.1021/bm401776z).<br /

Comment on “N-terminal Protein Tail Acts as Aggregation Protective Entropic Bristles: The SUMO Case”

International audienceSUMO-2 protein, SUMO-2 core domain, and the tail peptide corresponding to the first 14 residues were produced by chemical synthesis, and their secondary structures were analyzed by circular dichroism. The CD spectra of SUMO-2 and SUMO-2 core domain show distinct features and α-helical contents. In particular, the presence of the disordered tail in SUMO-2 lowers the α-helical content of the protein compared with SUMO-2 core domain and also explains the shift in the position of the minimum around 208 nm

Microfluidic Culture Model for Drug Screening on Schistosome Parasites

International audienceSchistosomiasis is a challenging parasitic model due to the absence of transgenic strains and systems allowing maintenance of heathy worms outside of their host (mammals). Classical in vitro studies (Petri dish) do not allow long-term survival of worm couples with retention of basic biological functions like mobility and pairing. We have designed a microfluidic device that sustainably cultivates adult worm couples. The influences of the composition and physical characteristics of mass flow on the mobility, pairing and long-term survival of worms have been studied. We have also assessed the effect of Praziquantel, the only therapeutic molecule currently in use

The Problem of Aspartimide Formation During Protein Chemical Synthesis Using SEA-Mediated Ligation

Aspartimide formation often complicates the solid phase synthesis of peptides. Much less discussed is the potential occurrence of this side-reaction during the coupling of peptide segments using chemoselective peptide bond forming reactions such as the native chemical ligation and extended methods. Here we describe how to manage this problem using bis(2-sulfenylethyl)amido (SEA)-mediated ligation and SUMO-2/SUMO-3 as protein targets.<br /

Redox-Controlled Chemical Protein Synthesis: Sundry Shades of Latency

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Total Chemical Synthesis of All SUMO-2/3 Dimer Combinations

International audienceOne hallmark of protein chemical synthesis is its capacity to access proteins that living systems can hardly produce. This is typically the case for proteins harboring post-translational modifications such as ubiquitin or ubiquitin-like modifiers. Various methods have been developed for accessing polyubiquitin conjugates by semi- or total synthesis. Comparatively, the preparation of small-ubiquitin-like modifier (SUMO) conjugates, and more particularly of polySUMO scaffolds, is much less developed. We describe hereinafter a synthetic strategy for accessing all SUMO-2/3 dimer combinations

The venus kinase receptor (VKR) family: structure and evolution.

International audienceBACKGROUND: Receptor tyrosine kinases (RTK) form a family of transmembrane proteins widely conserved in Metazoa, with key functions in cell-to-cell communication and control of multiple cellular processes. A new family of RTK named Venus Kinase Receptor (VKR) has been described in invertebrates. The VKR receptor possesses a Venus Fly Trap (VFT) extracellular module, a bilobate structure that binds small ligands to induce receptor kinase activity. VKR was shown to be highly expressed in the larval stages and gonads of several invertebrates, suggesting that it could have functions in development and/or reproduction. RESULTS: Analysis of recent genomic data has allowed us to extend the presence of VKR to five bilaterian phyla (Platyhelminthes, Arthropoda, Annelida, Mollusca, Echinodermata) as well as to the Cnidaria phylum. The presence of NveVKR in the early-branching metazoan Nematostella vectensis suggested that VKR arose before the bilaterian radiation. Phylogenetic and gene structure analyses showed that the 40 receptors identified in 36 animal species grouped monophyletically, and likely evolved from a common ancestor. Multiple alignments of tyrosine kinase (TK) and VFT domains indicated their important level of conservation in all VKRs identified up to date. We showed that VKRs had inducible activity upon binding of extracellular amino-acids and molecular modeling of the VFT domain confirmed the structure of the conserved amino-acid binding site. CONCLUSIONS: This study highlights the presence of VKR in a large number of invertebrates, including primitive metazoans like cnidarians, but also its absence from nematodes and chordates. This little-known RTK family deserves to be further explored in order to determine its evolutionary origin, its possible interest for the emergence and specialization of Metazoa, and to understand its function in invertebrate development and/or reproductive biology

A Cysteine Selenosulfide Redox Switch for Protein Chemical Synthesis

The control of cysteine reactivity is of paramount importance for the synthesis of proteins using the native chemical ligation (NCL) reaction. We discovered that this goal can be achieved in a traceless manner during ligation by appending a simple N-selenoethyl group to cysteine. While in synthetic organic chemistry the cleavage of carbon-nitrogen bonds is notoriously difficult, we found that N-selenoethyl cysteine (SetCys) loses its selenoethyl arm in water under mild conditions upon reduction of its selenosulfide bond. Detailed mechanistic investigations uncover a novel mode of reactivity for Cys. Its implementation in a process enabling the modular and straightforward assembly of linear or backbone cyclized polypeptides is illustrated by the synthesis of biologically active cyclic hepatocyte growth factor variants.<br /

Catalysis of Hydrazone and Oxime Peptide Ligation by Arginine

International audienceHydrazone and oxime peptide ligations are catalyzed by arginine. The catalysis is assisted intramolecularly by the side-chain guanidinium group. Hydrazone ligation in the presence of arginine proceeds efficiently in phosphate buffer at neutral pH but is particularly powerful in bicarbonate/CO2 buffer. In addition to acting as a catalyst, arginine prevents the aggregation of proteins during ligation. With its dual properties as a nucleophilic catalyst and a protein aggregation inhibitor, arginine hydrochloride is a useful addition to the hydrazone/oxime ligation toolbox