Jorge Sánchez‐Quesada

Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

ABSTRACT Cyclic peptides with an even number of alternating d,l-α-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 μg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-α-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

A Synthetic Pore-Mediated Transmembrane Transport of Glutamic Acid

Transported to the other side: Cyclic D,L-α-peptides self-assemble in lipid bilayers into transmembrane ion channels that may allow efficient transport of glutamic acid. The molecular transport is size/shape selective, as evidenced by the high transport rates observed with cyclodecapeptide-based transmembrane pores but not with the smaller cyclooctapeptide analogue.

Synthesis of Pre‐Organized Bisdiglycolamides (BisDGA) and Study of their Extraction Properties for Actinides(III) and Lanthanides(III)

Bisdiglycolamides 1–9 were synthesized and studied as extracting agents for An(III) and Ln(III) from nitric acid solutions. Compounds 1d‐3 with rigid spacers as m‐xylylene and 6b‐9 with more flexible alkyl chain linkers, show higher selectivity for Eu(III) extraction over Am(III) than diglycolamides (TBDGA, DMDODGA, TODGA) in (50:50)%Vol HPT/1‐octanol mixture. Am(III) and Eu(III) extraction kinetics are very fast and back‐extraction with more than 99% efficiency of both cations is possible after four times of contact of the loaded solvent with fresh 0.01 mol/L nitric acid solutions.

Total synthesis of non-natural compounds for molecular recognition. The double challenge

Molecular recognition of biomolecules by synthetic receptors requires modular assembly of various components to complement the molecular characteristics (sizes, topologies, and functional groups) of the substrate. A number of receptors for biorelevant molecules containing oxoanions have been assembled from a bicyclic chiral guanidine subunit. Several receptors accelerate or catalyze reactions proceeding through anionic transition states. Among the structures recently prepared, a receptor incorporating a calix(6)arene subunit has been developed, showing high affhity for phosphocholine derivatives. Chains of tetraguanidinium sulfates form double helices in solution. These substances strongly induce formation of a-helical conformations in Asp rich peptides.

Side chain elongation causes a change from enthalpy driven to entropy driven binding in the molecular recognition of tetraanionic peptides

In binding to tetraguanidinium compounds, the average side chain length of tetraanionic peptides determines the thermodynamics of binding, the degree of helix induction and the rigidity of the complex formed.

Bismalonamides (BISMA) as new extractants for Am(III) and Eu(III) from aqueous high-level wastes

Bismalonamides 1–8 and bisthiomalonamides 9–13 were synthesised and studied as extracting agents for Am(III) and Eu(III) from nitric acid solutions into organic solvents. Bismalonamides 7a and 7g display higher distribution coefficients in chlorinated solvents than single malonamide DMDOHEMA, suggesting that bismalonamides could pre-organise the binding groups around the cation more efficiently. Additionally, back-extraction of Am(III) and Eu(III) from a loaded organic solution of 7g in (50:50)% vol TPH/1-octanol mixture allowed to recover 99% of the initially extracted Am(III) and Eu(III) after three times of contact with fresh 0.01 mol/L nitric acid solutions.