Display Selection of a Hybrid Foldamer–Peptide Macrocycle

Expanding the chemical diversity of peptide macrocycle libraries for display selection is desirable to improve their potential to bind biomolecular targets. We now have implemented a considerable expansion through a large aromatic helical foldamer inclusion. A foldamer was first identified that undergoes flexizyme-mediated tRNA acylation and that is capable of initiating ribosomal translation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer–peptide hybrids. A hybrid macrocyclic nanomolar binder to the C-lobe of the E6AP HECT domain was selected that showed a highly converged peptide sequence. A crystal structure and molecular dynamics simulations revealed that both the peptide and foldamer are helical in an intriguing reciprocal stapling fashion. The strong residue convergence could be rationalized based on their involvement in specific interactions with the target protein. The foldamer stabilizes the peptide helix through stapling and through contacts with key residues. These results altogether represent a significant extension of the chemical space amenable to display selection and highlight possible benefits of inserting an aromatic foldamer into a peptide macrocycle for the purpose of protein recognition

Identification and Vibration Attenuation for the Parallel Robot Par2

International audiencePar2 is a two-degree-of-freedom parallel robot designed for high-speed and high-accuracy industrial pick-and-place operation tasks. As a result of the high acceleration trajec-tories, the end-effector undergoes some undesirable vibrations after reaching the stop positions, compromising its precision and leading therefore to an increase in the operation cycle time. Accelerometer sensors placed on the end-effector and piezoelectric patch actuators wrapped around the robot arms are employed in order to actively reduce these vibrations in a non-collocated closed-loop setting. After submitting the robot to an identification procedure, the obtained nominal model is used to synthesize a reduced order controller with the H ∞ Loop Shaping technique. Performance analysis as well as simulation and experimental results exhibit that vibration reduction is achieved around the nominal operating point, but fails for some extreme operating points, due to high control efforts. An anti-windup strategy is then employed to deal with the saturation of the actuator, which allows to achieve vibration attenuation on the whole operation domain, for a given configuration of the robot at the stop point

Novel in situ gelling ophthalmic drug delivery system based on gellan gum and hydroxyethylcellulose: Innovative rheological characterization, in vitro and in vivo evidence of a sustained precorneal retention time

International audienceAchieving drug delivery at the ocular level encounters many challenges and obstacles. In situ gelling delivery systems are now widely used for topical ocular administration and recognized as a promising strategy to improve the treatment of a wide range of ocular diseases. The present work describes the formulation and evaluation of a mucoadhesive and ion-activated in situ gelling delivery system based on gellan gum and hydroxyethylcellulose for the delivery of phenylephrine and tropicamide. First, physico-chemical characteristics were assessed to ensure suitable properties regarding ocular administration. Then, rheological properties such as viscosity and gelation capacity were determined. Gelation capacity of the formulations and the effect of hydroxyethylcellulose on viscosity were demonstrated. A new rheological method was developed to assess the gel resistance under simulated eye blinking. Afterward, mucoadhesion was evaluated using tensile strength test and rheological synergism method in both rotational and oscillatory mode allowing mucoadhesive properties of hydroxyethylcellulose to be point out. Finally, residence time on the ocular surface was investigated in vivo, using cyanine 5.5 dye as a fluorescent marker entrapped in the in situ gelling delivery systems. Residence performance was studied by non-invasive optical imaging on vigilant rabbits, allowing eye blinking and nasolacrimal drainage to occur physiologically. Fluorescence intensity profiles pointed out a prolonged residence time on the ocular surface region for the developed formulations compared to conventional eye drops, suggesting in vitro/in vivo correlations between rheological properties and in vivo residence performances

Display Selection of a Hybrid Foldamer-Peptide Macrocycle

A helical aromatic foldamer was identified that undergoes tRNA acylation by a flexizyme and ribosomal peptide initiation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer-peptide hybrids. A hybrid macrocyle binder to the C-lobe of the E6AP HECT domain was selected that showed highly converged peptide residues. A crystal structure and molecular dynamics simulations revealed that both the peptide and foldamer are helical in an intriguing reciprocal stapling fashion. The strong residue convergence could be rationalized based on their involvement in specific interactions. The foldamer stabilizes the peptide helix through stapling and through contacts with key residues. It appears to also contribute to protein binding by direct protein interactions. The results altogether highlight possible benefits in inserting an aromatic foldamer into a peptide macrocycle for the purpose of protein recognition