The beta2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1-mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.

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The retinoic acid-related orphan receptor ␣ (ROR␣) is an orphan member of the subfamily 1 of nuclear hormone receptors. Our recent structural and functional studies have led to the hypothesis that cholesterol or a cholesterol derivative is the natural ligand of ROR␣. We have now solved the x-ray crystal structure of the ligand binding domain of ROR␣ in complex with cholesterol-3-O-sulfate following a ligand exchange experiment. In contrast to the 3-hydroxyl of cholesterol, the 3-O-sulfate group makes additional direct hydrogen bonds with three residues of the ROR␣ ligand binding domain, namely NH-Gln 289 , NH-Tyr 290 , and NH1-Arg 370 . When compared with the complex with cholesterol, seven well ordered water molecules have been displaced, and the ligand is slightly shifted toward the hydrophilic part of the ligand binding pocket, which is ideally suited for interactions with a sulfate group. These additional ligand-protein interactions result in an increased affinity of cholesterol sulfate when compared with cholesterol, as shown by mass spectrometry analysis done under native conditions and differential scanning calorimetry. Moreover, mutational studies show that the higher binding affinity of cholesterol sulfate translates into an increased transcriptional activity of ROR␣. Our findings suggest that cholesterol sulfate could play a crucial role in the regulation of ROR␣ in vivo.The group of retinoic acid-related orphan nuclear receptors (ROR) 1 is encoded by three different genes (␣, ␤, and ␥) (1). ROR␣ has been implicated in numerous age-related phenotypes such as atherosclerosis, cerebellar atrophy, immunodeficiency, and bone metabolism (2). ROR␣ was still considered an orphan receptor until we recently reported the first crystal structure of the ROR␣ LBD. It had revealed a ligand that was unexpectedly present, namely cholesterol (3). We also had shown that the transcriptional activity of ROR␣ could be modulated by changes in intracellular cholesterol level or mutation of residues involved in cholesterol binding. This has led to the hypothesis that ROR␣ could play a key role in the regulation of cholesterol homeostasis and thus represents an important drug target in cholesterol-related diseases. Despite the relatively high homology between ROR␣ LBD and ROR␤ LBD (63%), cholesterol seems not to be a ligand for the ROR␤ isoform, as reported recently by . This indicates a possible distinct function for ROR␤ and ROR␣. An inspection of the x-ray structure of the complex between ROR␣ LBD and cholesterol had shown that in the hydrophilic part of the LBP, there is space for a substituent attached to the hydroxy group of cholesterol, if water molecules are displaced (3). The presence of three arginines (Arg 292 , Arg 370 , and Arg 367 ) and of two free backbone amide nitrogens (NH-Gln 289 and NH-Tyr 290 ) strongly suggested a negatively charged substituent with at least two hydrogen-bond acceptor functionalities. Docking studies led to the prediction that cholesterol sulfate should have higher affinity than cholest...

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

Octreotide, a synthetic somatostatin analogue, is an octapeptide with one disulfide bridge. Crystals of octreotide are orthorhombic, space group P212121, a = 18.458 (5), b = 30.009 (7), c = 39.705 (27) A, with three molecules of octapeptide, one ordered oxalate dianion and 52 water molecules in the asymmetric unit. Complete protonation of the NH2 groups (as assumed in the refinement) would require three oxalate dianions in the asymmetric unit for charge neutrality; a chemical analysis indicated that four are present. In either case they are so disordered that they cannot be distinguished from the water molecules. The 18 951 unique reflections (Rsy m = 0.026) used for structure solution and refinement were recorded with the EMBL imaging-plate scanner using synchrotron radiation. The structure was solved by Patterson interpretation, locating the three disulfide bridges, followed by tangent phase expansion and EFourier recycling. The anisotropic refinement against all F 2 data between 1.04 and 10.0 A resolution by blocked restrained full-matrix least-squares techniques converged to a conventional R index based on F of 0.084 [I > 2a(/) and 10.0 > d > 1.04 A] and wR2, the weighted R-index on F 2, of 0.246 (for all data). One peptide molecule adopts a flat ~-sheet structure; the other two possess different irregular backbone conformations, but are similar to each other. All three molecules have a distorted type II'/3-turn around the o-Trp-Lys region, but exhibit different sidechain conformations. The crystal structure is stabilized by a network of inter-and intramolecular hydrogen bonds.