EWI-2/CD316 is an inducible receptor of HSPA8 on human dendritic cells.

The activation of dendritic cells is marked by changes both on their cell surfaces and in their functions. We define EWI-2/CD316 as an early activation marker of dendritic cells upregulated by Toll-like receptor ligands clearly before CD86 and CD83. By expression cloning, human heat shock protein A8 (HSPA8), a member of the hsp70 family, was identified as the ligand for EWI-2.

Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus.

Using a newly developed model of allergic contact dermatitis in pigs, calcineurin inhibitors of the tacrolimus and ascomycin type were shown to have a highly anti-inflammatory action after topical application. These findings provided the first pharmacological evidence of the efficacy of this novel class of topical agents in the treatment of inflammatory skin diseases, and, thus, their potential to become the first alternative to corticosteroids in more than 40 years. As a result of a large research program into ascomycins, pimecrolimus (Elidel(R), SDZ ASM 981) was selected for development due to its favorable pharmacology and safety profile, alongside tacrolimus (Protopic(R), FK 506).

Analyzing the performance of conformational search programs on compound databases.

We have studied the sampling performance of conformational search programs using geometric and energetic criteria. Ideally, a conformational search algorithm should identify the largest possible number of low-energy structures (energy criterion) covering the widest possible range of molecular shapes (geometric criterion). Geometric analysis consisted in comparing the distribution of conformations within the generated ensembles by multidimensional scaling and by analysing the eigenvalue structure of the pairwise coordinate covariance matrices.

A novel low molecular weight inhibitor of dendritic cells and B cells blocks allergic inflammation.

Rationale And Objective: During allergic lung inflammation dendritic cells (DCs) direct the generation and function of effector T-helper type 2 cells. T-helper type 2 cells not only orchestrate the inflammatory processes in the tissue by inducing the accumulation and activation of proinflammatory cells but also induce IgE production by B cells. Thus, inhibitors of DC function should have therapeutic benefits in patients with allergies.

Pimecrolimus permeates less than tacrolimus through normal, inflamed, or corticosteroid-pretreated skin.

The permeabilities of normal human and normal, inflamed, or corticosteroid (CS) pretreated skin of young domestic pigs for pimecrolimus and tacrolimus were compared in vitro, using Franz-type diffusion cells. The test articles were either used as 1.0% solutions or as the marketed formulations (Elidel 1% cream, Protopic 0.

SH2 binding site comparison: a new application of the SURFCOMP method.

To avoid side effects, it is often desirable to increase the specificity of a drug candidate when targeting one member of a family of related proteins, whereby one exploits small differences between the structures of the binding sites. Identification of such differences can be carried out by analyzing the distributions of physicochemical properties mapped onto molecular surfaces. Here we demonstrate that SURFCOMP, our local surface similarity detection method, is able to detect differences between the binding sites of two closely related proteins.

The effect of RNA secondary structures on RNA-ligand binding and the modifier RNA mechanism: a quantitative model.

RNA-ligand binding often depends crucially on the local RNA secondary structure at the binding site. We develop here a model that quantitatively predicts the effect of RNA secondary structure on effective RNA-ligand binding activities based on equilibrium thermodynamics and the explicit computations of partition functions for the RNA structures. A statistical test for the impact of a particular structural feature on the binding affinities follows directly from this approach.

mRNA openers and closers: modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure.

Approximately 3 000 genes are regulated in a time-, tissue-, and stimulus-dependent manner by degradation or stabilization of their mRNAs. The process is mediated by interaction of AU-rich elements (AREs) in the mRNA's 3'-untranslated regions with trans-acting factors. AU-rich element-controlled genes of fundamentally different functional relevance depend for their activation on one positive regulator, HuR.

Steroid sulfatase inhibitors.

Steroid sulfatase (STS) regulates the local production of estrogens and androgens from systemic precursors in several tissues. The enzyme catalyzes the hydrolysis of the sulfate esters of 3-hydroxy steroids, which are inactive transport or precursor forms of the active 3-hydroxy steroids. STS inhibitors are expected to block the local production and, consequently, to reduce the local levels of the hormones.