The adjuvant monophosphoryl lipid A increases the function of antigen-presenting cells

The induction of immune responses in vivo is typically performed with antigens administered in external adjuvants, like alum, complete Freund's adjuvant, LPS and, more recently, monophosphoryl lipid A (MPL). However, the role of the adjuvant is still poorly defined. The aim of this study was to test whether the MPL affects the function of antigen-presenting cells (APC) in vitro and in vivo. Antigen-pulsed APC [including macrophages, B cells and dendritic cells (DC)] were incubated or not with MPL, and their ability to sensitize naive T cells was tested in vitro and in vivo. The data show that MPL enhances the ability of macrophages and B cells to sensitize naive T cells, and confers to them the capacity to induce the development of T(h)1 and T(h)2. Administration of MPL i.v. in mice results in the redistribution of fully mature DC in the T cell area of the spleen. These observations suggest that MPL may induce an antigen-specific primary immune response by provoking the migration and maturation of DC that are the physiological adjuvant of the immune system.     

New trends in the design of drugs against Alzheimer's disease

First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors, based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD.     

Herpes simplex virus (HSV) type 2 glycoprotein D subunit vaccines and protection against genital HSV-1 or HSV-2 disease in guinea pigs

In two recent clinical trials, a vaccine containing herpes simplex virus (HSV) type 2 glycoprotein D (gD2) and a novel adjuvant AS04 comprising alum (Al) and 3-deactylated monophosphoryl lipid A (3-dMPL) afforded HSV-seronegative women significant protection against HSV-2 genital disease (vaccine efficacy, 73% in study 1 and 74% in study 2) and limited protection against infection (46% in study 1 and 39% in study 2). In the present report, studies in the guinea pig model investigated the protection afforded by gD2/AS04 against HSV-1 and HSV-2 genital herpes and investigated whether immunization could prevent or reduce recurrent disease in guinea pigs that developed mucosal infection. Immunization with gD2/AS04 conveyed nearly complete protection against primary disease with either virus but did not prevent mucosal infection. Guinea pigs immunized with gD2/AS04 were significantly better protected against recurrent disease than were guinea pigs immunized with a gD2/Al vaccine, which suggests that inclusion of 3-dMPL improved protection against latent infection.     

Chiral resolution, pharmacological characterization, and receptor docking of the noncompetitive mGlu1 receptor antagonist (+/-)-2-hydroxyimino- 1a, 2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic acid ethyl ester

Racemic CPCCOEt ((1aRS,7aRS)-2-hydroxyimino-1a, 2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic acid ethyl ester, (+/-)-1) derivatives have been shown to be subtype-selective metabotropic glutamate (mGlu) 1 receptor antagonists (Annoura et al. Bioorg. Med. Chem. Lett. 1996, 6, 763-766). The optical isomers of (+/-)-1 have been separated by chromatography on a chiral stationary phase. The absolute configuration at the C-1a and C-7a positions was determined using X-ray crystallography of an amide derivative with the methyl ester of L-phenylalanine (L-PheOMe) ((+)-6). In a phosphoinositol (PI) turnover assay at the cloned human mGlu1b receptor, (-)-1 and the new amide derivatives (-)-5 and (-)-6, all of which have (1aS,7aS)-stereochemistry on the chromane ring system, showed IC(50) values of 1.5, 0.43, and 0.93 microM, respectively. In contrast, (+)-1 and the new amide derivatives (+)-5 and (+)-6were found to be inactive up to a concentration of 30 microM indicating a selectivity for the (-)-enantiomers of at least 70-fold. In a previous study (Litschig et al. Mol. Pharmacol. 1999, 55, 453-461) we demonstrated using site-directed mutagenesis that the interaction site of (+/-)-1 is located in the transmembrane (TM) domain of hmGlu1b. To suggest a plausible binding mode of (-)-1, we have built a molecular mechanics model of the putative seven TM domain of hmGlu1 based on the alpha-carbon template of the TM helices of rhodopsin. A receptor docking hypothesis suggests that the OH of T815 (TMVII) comes in close contact with the oxime OH of (-)-1 and (-)-5, whereas no such close interactions could be demonstrated by docking of (+)-1.     

Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer

In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support. The absolute stereochemistry was determined by X-ray diffraction.     

Synthesis and biological activity of 2-lactonyl penems

A series of potent antibacterial agents have been prepared. These agents are penems carrying a lactone ring in the C-2 position. Excellent activity against Gram-positive and Gram-negative organisms--except Pseudomonas aeruginosa--was found.     

Umbilical cord pseudocyst in trisomy 18

Prenatal diagnosis of cord defects by means of ultrasound examination is possible and highly accurate. Although this is a rare pathological finding, we report two cases in which umbilical cord pseudocysts were associated with trisomy 18. These observations underscore the need of umbilical blood sampling for establishing the karyotype in fetuses with such umbilical cord anomalies and the importance of careful examination of placentas and infants born with such defects.     

Orally bioavailable competitive CCR5 antagonists

The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models.     

A treatment of non-ketotic hyperglycinaemia

The treatment comprising a special diet (without glycine, serine, and with a reduced amount of threonine), strychnine nitrate and ursodesoxycholic acid (UDCA) led to normoglycinaemia in this form of severe nonketotic glycine encephalopathy. Diet and treatment were well tolerated but without significant effect upon psychomotor development. This treatment should be more effective if administered before irreversible brain damage occurs, particularly in moderate and chronic forms of NKH.