Current Topics in Medicinal Chemistry - Volume 3, Issue 12, 2003

For proteins that are found in organisms ranging from bacteria to humans the clear delineation of the cellular function of immunophilins has run a tortuous path which in some ways appears little closer to its final destination. (Galat pp 1315-1349) This journey has been marked by many waypoints along the road that at each stage has given rise to a new nomenclature for these ubiquitous proteins. The scientific odyssey b Read More

The observation by Von Euler and Gaddum in 1931 that an extract of horse intestine and brain causes peripheral vasodilatation and contraction of intestinal muscles set stage for a number of studies which ultimately lead to the determination of the amino acid sequence of the first member of mammalian tachykinins namely substance P in 1971. Since then two additional tachykinins from mammalian source, neurokinin A and n Read More

Information recovered from genome sequencing projects, multiple sequence alignments, structural analyses of PPIase and published records were used in deciphering the biological diversity, functions and targets of four groups of proteins encoded by dissimilar sets of sequences whose spatial representations exhibit peptidylprolyl cis / trans isomerase activity (PPIase). In the human genome there are encoded fifteen proteins w Read More

The immunophilin cochaperones, cyclophilin 40 (CyP40), FKBP51 and FKBP52 and PP5, a serine / threonine protein phosphatase, have been implicated as modulators of steroid receptor function through their association with Hsp90, a molecular chaperone with a key role in steroid hormone signalling. Although progress towards a satisfying definition for the role of these components in steroid receptor complexes ha Read More

It is well established that the immunosuppressive effects of cyclosporin A (CsA) and FK506 (also known as tacrolimus) are mediated through binding to their cognate cellular proteins cyclophilin and FKBP (collectively termed immunophilins), respectively. Biochemical analysis had revealed that cyclophilin-CsA and FKBP-FK506 complexes bind to and inactivate Ca2+- dependent serine / threonine phosphatase calcineurin. Since ca Read More

FK506 (tacrolimus), initially developed as an immunosuppressant drug, represents a class of compounds with potential high impact for the treatment of human neurological disorders. While immunosuppression is mediated by the 12-kD FK506-binding-protein (FKBP-12), the neurite elongation activity of FK506 involves FKBP-52 (also known as FKBP-59 or Hsp-56), a component of mature steroid receptor complexes: F Read More

Immunophilins are receptors for immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their non- immunosuppressive analogs, which are collectively referred to as “immunophilin ligands” (IPL). Cyclosporin A binds to a class of IP called cyclophilins, whereas the receptors for FK506 and rapamycin belong to the family of FK506- binding proteins (FKBP). The latter are designated according to their molecular weight: FK Read More

The ryanodine receptor (RyR) is the major calcium (Ca2+) release channel in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle and is required for excitation-contraction (EC) coupling. The 565 kDa RyR protein forms a tetrameric channel that is part of a macromolecular signaling complex that also includes four FK506 binding proteins (FKBPs). The RyR channel complex is localized on specialized regions of the SR, s Read More

This review includes an analysis of available X-ray and NMR structures of both members of the immunophilin family; cyclophilins and the FK-506 binding proteins (FKBPs). Available structures are compared and contrasted to highlight different structural features seen both within and between species. Each immunophilin family has been structurally characterised with a variety of small molecule ligands, principally immunosuppr Read More

The mammalian tachykinin (TK) peptides and their three neurokinin (NK) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests pathophysiological relevance for TKs in various diseases including asthma, emesis and depression. The promiscuous TK-NK rec Read More

The study of tachykinin NK1 (substance P) receptor antagonists has emerged as a field of great promise due to accumulating evidence that NK1 antagonists offer possible new treatment options in therapeutic areas ranging from pain, emesis, and pulmonary disorders to depression and anxiety. It is hoped that the unique mechanism of action of these agents, which involves modulation of effects mediated by the interacti Read More

The search for new NK2 receptor antagonists have resulted in the discovery of several different classes of compounds with promise to have clinical utility. Clearly, the first reported non-peptide NK2 receptor antagonist (SR- 48,968) has inspired a lot of effort in the area, but over the years other approaches have also been fruitful. These include optimisation of hits from random screening and modifying compounds with NK3 rece Read More