Anti-chemokine small molecule drugs: a promising future?

Importance Of The Field: Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry.

Areas Covered In This Review: Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field.

Structural basis of chemokine sequestration by a tick chemokine binding protein: the crystal structure of the complex between Evasin-1 and CCL3.

Background: Chemokines are a subset of cytokines responsible for controlling the cellular migration of inflammatory cells through interaction with seven transmembrane G protein-coupled receptors. The blocking of a chemokine-receptor interaction results in a reduced inflammatory response, and represents a possible anti-inflammatory strategy, a strategy that is already employed by some virus and parasites. Anti-chemokine activity has been described in the extracts of tick salivary glands, and we have recently described the cloning and characterization of such chemokine binding proteins from the salivary glands, which we have named Evasins.

A straightforward, one-pot protocol for the synthesis of fused 3-aminotriazoles.

A simple protocol for the synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines is reported. The newly developed one-pot methodology involves the reaction of hydrazinopyridine with isothiocyanates to give the corresponding thiosemicarbazides, which are further desulfurized in situ using polymer-supported Mukaiyama's reagent to promote the final cyclization and formation of the central core. Aryl isothiocyanates bearing both electron-donating and electron-withdrawing groups are well tolerated, and the expected compounds were obtained in excellent purities and yields after removal of salts with a SPE-NH2 column.

An efficient and expeditious synthesis of di- and trisubstituted amino-phenyl and -benzyl derivatives of tetrazole and [1,3,4]oxadiazol-2-one.

A practical protocol for the parallel synthesis and purification of amino tetrazole and [1,3,4]oxadiazol-2-one derivatives as carboxylic acid bioisosteres is described. Phenyl- and benzyl-amines, substituted with tetrazole or [1,3,4]oxadiazol-2-one, were transformed into functionally diverse and novel compounds, with p K a values ranging from 4.9 to 8.

ExactFDR: exact computation of false discovery rate estimate in case-control association studies.

Genome-wide association studies require accurate and fast statistical methods to identify relevant signals from the background noise generated by a huge number of simultaneously tested hypotheses. It is now commonly accepted that exact computations of association probability value (P-value) are preferred to chi(2) and permutation-based approximations. Following the same principle, the ExactFDR software package improves speed and accuracy of the permutation-based false discovery rate (FDR) estimation method by replacing the permutation-based estimation of the null distribution by the generalization of the algorithm used for computing individual exact P-values.

Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists.

In the course of a high throughput screening, a series of pyrazole compounds were identified with luteinizing hormone receptor (LH-R) agonist activity. A focused pyrazole library was produced by solid-phase synthesis and key pyrazole regioisomers were obtained selectively in solution. Evaluation of those compounds in a cAMP assay in CHO cells transfected with h-LH receptor allowed us to propose a structure-activity relationship model for this series and led to the identification of the first low molecular weight molecule with in vitro activity in a Leydig cells assay (ED(50)=1.