Biocompatible poly(methylidene malonate)-made materials for pharmaceutical and biomedical applications.

In the past 20 years, mainly with the sponsorship of Laboratoires UPSA (France) and, afterwards, its spin-off company Virsol (France), several authors have studied methylidene malonate-based polymers used in drug delivery approaches and in the development of novel biomaterials. The present paper aims at summing up the preparation of methylidene malonate monomers, and essentially a novel asymmetric diester structure: 1-ethoxycarbonyl-1-ethoxycarbonylmethylenoxycarbonyl ethene named methylidene malonate 2.1.2. Their polymeric and copolymeric derivatives and a few of their applications which were reported in the literature are also presented. It encompasses the manufacturing of particulate systems such as nano- and macroparticles designed for the delivery of hydrophilic or hydrophobic drugs and biomolecules. This review article also describes their use as biomaterials of interest in the fields of tissue repair, as drug reservoirs or ophthalmology, as implants. Copolymers based on these monomers offer a large range of properties and could be used as new surfactants, micellar vectors, or particulate systems for gene delivery. Therefore, this review, certainly the first dedicated exclusively to methylidene malonate-based materials, highlights the great biomedical and pharmaceutical technology potential of these new materials.

Structural and immunological characterisation of heteroclitic peptide analogues corresponding to the 600-612 region of the HIV envelope gp41 glycoprotein.

The conformational and immunological properties of different analogues corresponding to the 600-612 disulfide loop of the human immunodeficiency virus (HIV) gp41 glycoprotein envelope were studied. Fourteen analogues were designed and synthesised; namely, a series of seven analogues in which the disulfide bond was replaced by a lactam bridge and a series of seven analogues in which one residue of each analogue at a time, was replaced by its corresponding homologised alpha-amino acid (beta(3)-amino acid). In the case of the lactam analogues, the influence of the two possible CO-NH and NH-CO orientations of the lactam bridge as well as the size of the lactam ring was explored. The analogues were tested in ELISA with monoclonal antibodies raised against the 600-612 cyclic parent peptide as well as with sera from HIV-1 infected patients. A structural analysis of the parent and analogue peptides was carried out in dimethyl sulfoxide (DMSO-d(6)) using two-dimensional NMR techniques and molecular dynamics simulations. Comparison of the own conformation of the cyclic analogues with their either strong or weak reactivity with the antibodies reveals structural features that may be correlated with the antibody reactivity. Thus, a close structural similarity, particularly a characteristic orientation of the side-chains of residues Lys606, Leu607 and Ile608 in the loop, was found in certain beta(3)-analogues that were better recognised than the parent peptide by anti-peptide mouse monoclonal antibodies and patients' antibodies.

A synthetic triacylated pseudo-dipeptide molecule promotes Th1/TReg immune responses and enhances tolerance induction via the sublingual route.

In this study, we tested two triacylated pseudo-dipeptidic molecules, OM-197-MP-AC and OM-294-BA-MP as candidate adjuvants for allergy vaccines. Both molecules induce human dendritic cell (h-DC) maturation and polarize naïve T cells toward the Th1 type with IFNgamma production. Only OM-294-BA-MP induces IL10 gene expression both in monocyte-derived DCs and CD4+ naïve T cells. Sublingual administration of OM-294-BA-MP plus the antigen enhances tolerance induction in BALB/c mice with established asthma to ovalbumin with an impact on both airways hyperresponsiveness and lung inflammation. Given its Th1/Treg polarizing properties, OM-294-BA-MP is a valid candidate for sublingual allergy vaccines.

Synthesis and characterization of poly(ethylene oxide)-block-poly(methylidene malonate 2.1.2) block copolymers bearing a mannose group at the PEO chain end.

A poly(ethylene oxide)-block-poly(methylidene malonate 2.1.2) block copolymer (PEO-b-PMM 2.1.2) bearing a mannose moiety at the poly(ethylene oxide) chain end was synthesized by sequential anionic polymerization of ethylene oxide (EO) and methylidene malonate 2.1.2 (MM 2.1.2), followed by a coupling reaction between its poly(ethylene oxide) amino- or aldehyde-end group and a sugar derivative. Different coupling procedures, either in organic media or in aqueous micellar solutions, were examined in order to optimize the poly(ethylene oxide) end-glycosylation yield. The micellar size of the functionalized block copolymers was determined by dynamic light scattering.

DEUSS: a perdeuterated poly(oxyethylene)-based resin for improving HRMAS NMR studies of solid-supported molecules.

A novel resin called DEUSS (perdeuterated poly(oxyethylene)-based solid support) has been prepared by anionic polymerization of deuterated [D4]ethylene oxide, followed by cross-linking with deuterated epichlorohydrin. DEUSS can be suspended in a wide range of solvents including organic and aqueous solutions, in which it displays a high swelling capacity. As measured by proton HRMAS of the swollen polymer, the signal intensity of the oxyethylene protons is reduced by a factor of 110 relative to the corresponding nondeuterated poly(oxyethylene)poly(oxypropylene) (POEPOP) resin, thus facilitating detailed HRMAS NMR studies of covalently linked molecules. This 1H NMR invisible matrix was used for the solid-phase synthesis of peptides, oligoureas, and a series of amides as well as their characterization by HRMAS NMR spectroscopy. On-bead NMR spectra of high quality and with resolution comparable to that of liquid samples were obtained and readily interpreted. The complete absence of the parasite resin signals will be of great advantage, for example, for the optimization of multistep solid-phase stereoselective reactions, and for the conformational study of resin-bound molecules in a large variety of solvents.