Current Medicinal Chemistry - Volume 18, Issue 35, 2011

Tissue and organ transplantation constitute the main medical advances of the last century, and has been possible thanks to the contribution of doctors like Loix Roux, who, in 1885, firstly described a technique consisting on tissue culture ex vivo, or Emerich Ullman and Max Lederer, whose publications in 1914 collected all preliminary surgical advances in the field. These pioneers soon realized the need to avoid the interference of the immunological system in order to obtain successful allotropic organ transplantation. At the beginning of the 80's, cyclosporin (CsA), previously isolated and characterized in 1969 from the fungus Tolypocladium inflatum, became a miracle treatment to avoid organ rejection. After its discovery as an effective immunossupresor, several alternative treatments have been established, including another macrolide lactone derivate known as FK506, which was isolated from Streptomyces tsukubaensis, and firstly described in 1987. Soon after, scientists, upon discovering the intracellular molecular targets of these immunosuppressants, defined a new family of proteins known as immunophilins. Today, the immunophilin family has been subdivided into three main categories attending its sensitivity to immunosuppressants: cyclophilins, FKBPs and an additional uncharacterized CsA- and FK506-binding proteins subfamily. The most relevant functional property of immunophilins is their chaperone activity or peptidyl prolyl isomerase activity (PPI), which results inhibited upon complexing either with CsA or FK506. In this sense, the immunophilin chaperone activity is crucial for the correct folding and subsequent activation of many intracellular regulatory proteins. Moreover, many cellular functions attributed to this family involve interaction, and formation of heterotrimeric complexes, with the serine/threonine phosphatase calcineurin (CNa or PP2B). The latter contributed to misleadingly believe that CsA and FK506 are specific CNa inhibitors. In the last decades of the last century, scientists discovered the relevance of the serine/threonine kinase mTOR in cell cycle proliferation, cancer, apoptosis, and immunossuppression. The study of the cellular molecular target of rapamycin, revealed that, as for CsA and FK506, rapamycin and some of its derivates complexed with an immunophilin isotype and, subsequently, acquired the ability to complex with mTOR and reduced its kinase activity. The reviews in the present hot topic contribute to a better understanding of this important family of proteins. In fact, after the detailed historical review of transplants by Cubero and collaborators, authors describe several alternative strategies to the use of immunophilin antagonists, in order to avoid graft rejection once the medical procedures take place. Cubero and his team have supervised kidney transplant in the Infanta Cristina Hospital for more that 20 years and explain the latest protocol of immunosupression used nowadays. The structure and multiple cellular functions of immunophilins are detailed by Christian Lucke and Matthias Weiwad. These authors describe in detail the structure of the two major immunophilin groups, cyclophilins and FKBPs. The residues targeted during CsA and FK506 interaction with the peptidyl-prolyl isomerase active domain of immunophilins are analyzed in detail. Lucke and Weiwad further review some of the most relevant cellular events where immunophilins have been involved. Dr. Hausch provides the readers with an updated list of chemical tools used to prevent immunophilin activity. His group has been involved in the development of fluorescent derivates to explore the role of immunophilins in several cellular processes. The structure of the molecules is completed with a wide number of references in which these compound have been tested, thus providing a detailed information of the cellular behaviour of each compound. A new technical application to these compounds has also been suggested, which consist in the use of immunophilin binding agents to produce protein dimerization, thus receiving the name of chemical dimerizers. The involvement of immunophilins in neurodegenerative disorders is summarized by Dr Yoon et al. Since a neurotrophic effect was attributed to FK506 and rapamycin, the role of immunophilins in neurons has received much attention, and resulted in the demonstration that immunophilins participate in neurone growth, protection against oxidant insults, and neurotransmitter release. This review also summarizes the latest information regarding the role of different immunophilins in severe neurological diseases such as Parkinson, Alzheimer, Huntington, and amyothrophic lateral sclerosis disease. This review is complemented by that of Park and coworkers, which directly defines neuroimmunophilin ligands (NILs) as all immunophilin antagonists with neurological regulatory properties, and summarizes the current experimental evidences supporting the beneficial effects of NILs administration.....

Since the first attempt to replace a dysfunctional organ, clinics and scientific had to overcome many setbacks in order to warrant the success and viability of both the organ and the receptor. Despite the improvement of surgical procedures, some grafts fail within the following days or week due to immunologic rejection. Many ongoing researches are still seeking the perfect immunossupresors. Calcineurin targeting agents have been consolidated as a worldwide immnunossupressant therapy, but due to its widely functional role in many cell types, this strategy often represents a highly risk therapy due to side effects observed with these agents. Here we summarized the latest and past knowledge regarding immunossupression therapies, including the promising and widely used Immunophilin-targeting antagonist therapies.

The immunophilins are proteins which are capable of influencing the immune response in combination with an immunosuppressive drug. Their natural function, however, is mainly the cis/trans isomerization of peptidyl-prolyl bonds in other proteins. This review lists all immunophilin structure coordinates currently available in the RCSB protein data bank and highlights the key active-site factors that define their catalytic and immunological action. In addition, an overview of biologically-relevant functions is provided for various immunophilin members.

The immunophilin ligands cyclosporin A, FK506 and rapamycin are best known for their immunosuppressive properties and their clinical use in transplantation medicine. These compounds or their analogs are also clinically used or investigated in various types of cancer, coronary angioplasty, dermatology, hepatitis C infections, and neuroprotection. Furthermore, the role of immunophilins in various pathologies is increasingly being recognized, supporting the preclinical drug development for novel immunophilin targets. Finally, immunophilin ligands are widely used as sophisticated tools in chemical biology. This review shows the progress on three major areas made in the last five years. An update of the immunosuppressive ligands and their clinical applications is discussed in the first part of the review, followed by a discussion about the emerging immunophilin targets and their respective ligands. The final section gives a detailed assessment of immunophilin ligand-based tools.

Protein misfolding has been implicated in the pathophysiology of several neurodegenerative ‘amyloidoses’ that includes Alzheimer's, Parkinson's, Huntington's disease, frontotemporal dementia and amyotrophic lateral sclerosis. Accumulation of misfolded proteins into ordered fibrillar intra- or extracellular amyloids results in brain lesions that in turn lead to injury and neuronal loss. The appearance of protein aggregates in the diseased brain hints at an inability of cellular chaperones to properly assist folding of client proteins. Not surprisingly, studies involving cell-based and animal models of the neurodegenerative diseases have shown that overexpression of molecular chaperones can provide neuroprotection. Together with identification of new targets for symptomatic relief of motor and non-motor defects in neurodegenerative disorders, there is a critical unmet clinical need for the development of novel neuroprotective molecules. One such promising class of compounds are neuroimmunophilin ligands (NILs). Derived from FK506 (tacrolimus), NILs have been shown to be efficacious in a number of neurodegenerative disorders. The ability of these nonimmunosuppressive NILs to protect neurons is modulated, in part, by a large family of co-chaperone proteins called the FK506 binding proteins (FKBPs). This review focuses on the roles of FKBPs in neurodegenerative disorders with an emphasis on the cellular mechanisms responsible for their neuroprotective and neurotrophic activities. We discuss the structural features of FKBPs and the mode of action of NILs. For brevity, we limit our discussion to those FKBPs that are particularly enriched in the nervous system. We hope that such information will aid in the rational design of new and improved NILs for ameliorating neurodegenerative disorders.

In case of nervous damages, like nervous system trauma or various neurodegenerative diseases such as dementia or Parkinson, several treatments are available to restore neurological function. In spite of these treatments, results are often insufficient or not satisfactory in many neurologic diseases, especially for central nervous system (CNS) lesions. To minimize neurological dysfunction, it is critical to reduce neuronal death, avoiding loss of the synaptic connections, and securing viable neurons to extend axons. Unfortunately, there are no effective strategies to fulfill these basic needs except for some cases of peripheral neural damage up to now. Rescue of damaged neurons, stimulation of neurogenesis and transplantation of nervous tissue are strategies proposed to prevent neurodegenerative disorders. A number of studies have recently reported successful axon regeneration and neurological recovery by using immunosuppressants, such as FK506. Immunosuppressants act as excellent agents for enhancing the rate and extent of axon regeneration and neurological recovery. FK506 and other neuroimmunophilin ligands (NILs) might reverse neuronal degeneration. In several animal models mimicking Parkinson's disease, dementia and surgical damage, NILs induces resprouting, by acting as neurotrophic agents and preventing nerve damage, although more studies are necessary to identify new NILs with neuroprotective action, but lacking the side immunological effects observed in the ligands analyzed to date. This review explores the new clinical role of immunosuppressants in the treatment of nerve surgery of autologous, allografts or xenografts. Results of studies regarding immunosuppressant treatment of nervous system trauma and neurodegenerative diseases, like neurogenic erectile dysfunction, will be here considered.

Immunophilins belong to a highly conserved family of proteins with cis-trans peptidyl-prolyl isomerase activity, generally classified by their ability to selectively bind specific immunosuppressive drugs, thereby regulating their activity. Immunophilins include Cyclophilins (CyPs), which are specific targets of the immunosuppressant drug cyclosporin A (CsA); FKBPs (FK506-binding proteins), that are sensitive to both FK506 (tacrolimus) and rapamycin (sirolimus); and FCBPs which are sensitive to CsA and FK506. Immunophilins are expressed in multiple human tissues, including brain, heart, kidney, liver and lung and regulate functions as diverse as intracellular calcium signaling, protein transport, protein folding and gene transcription. In particular, immunophilins play key functional roles in the cardiovascular system, where they can associate with proteins such as ryanodine and IP3 receptors (RyR and IP3R), calcineurin, and mitochondrial permeability transition pore (MPTP) and Heat-shock proteins-caveolin-cholesterol complex and regulate their function. The biological importance of immunophilins is further revealed by the pathophysiology, as they have been implicated in several cardiovascular diseases, including vascular stenosis, atherosclerosis, heart failure and arrhythmias. This review summarizes some of the most recent studies on immunophilins and focuses on their roles in the mechanisms underlying the cardiovascular disease.

The immunophilin family includes a large group of proteins with peptidyl prolyl-isomerase activity (PPI-ase). Immunophilins chaperone activity has been documented to be crucial for the correct folding and activation of many proteins. Thus, they have been subjected of intense investigation since they were firstly described in the last decades of the past century. Many of these studies have been focused on leukocyte constitutively expressed immunophilins, due to their relevance in the correct folding, and subsequently, sensitization and activation of the glycoprotein receptor (RGBs) of lymphocyte T CD4+ and Treg, hence regulating immunological responses against pathogen insults. Several clinical trials have been completed in the last decade reporting that administration of immunophilin-binding drugs, derived from macrolide lactones, like cyclosporine A (CsA) and tacrolimus (FK506), induced successful results in preventing organ rejection. By contrast, the expression of immunophilins and their physiological function remain poorly investigated in others cell types, such as platelets, where a reduced number of studies presenting evidences of immunophilins expression and their physiological contribution have been published, despite a number of clinical trials have noticed side effects of these drugs in thrombosis and platelet count, thus suggesting a possible regulatory function of immunophilins in human platelets, which is reviewed here.

FK506 binding protein 51 (FKBP51) is an immunophilin physiologically expressed in lymphocytes. Very recently, aberrant expression of this protein was found in melanoma; FKBP51 expression correlates with melanoma aggressiveness and is maximal in metastatic lesions. FKBP51 promotes NF-κB activation and is involved in the resistance to genotoxic agents, including anthracyclines and ionizing radiation. FKBP51 is a cochaperone with peptidyl-prolyl isomerase activity that regulates several biological processes through protein-protein interaction. There is increasing evidence that FKBP51 hyperexpression is associated with cancer and this protein has a relevant role in sustaining cell growth, malignancy, and resistance to therapy. There is also evidence that FKBP ligands are potent anticancer agents, in addition to their immunosuppressant activity. In particular, rapamycin and its analogs have shown antitumor activity across a variety of human cancers in clinical trials. Although, classically, rapamycin actions are ascribed to inhibition of mTOR, recent studies indicate FKBP51 is also an important molecular determinant of the drug's anticancer activity. The aim of this article is to review the functions of FKBP51, especially in view of the recent findings that this protein is a potential oncogene when deregulated and a candidate target for signaling therapies against cancer.

Drugs currently used for the treatment of Alzheimer's disease (AD) produce limited clinical benefits, and there is no diseasemodifying therapy yet available. Compounds that inhibit or modulate γ-secretase, the pivotal enzyme that generates β-amyloid (Aβ), are potential therapeutics for AD. This article briefly reviews the profile of γ-secretase inhibitors and modulators that have reached the clinic. Studies in both transgenic and non-transgenic animal models of AD have indicated that γsecretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after prolonged administration. γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen, skin, and decrease in lymphocytes and alterations in hair color in experimental animals and in man, effects believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effect of the drug. These detrimental effects were mainly ascribed to the inhibition of the processing of an unknown substrate of γ-secretase. It has been also hypothesized that the detrimental cognitive effects observed after semagacestat administration are due to the accumulation of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of amyloid precursor protein, APP, or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Some non-steroidal anti-inflammatory drugs and other small organic molecules have been found to modulate γsecretase shifting its cleavage activity from longer to shorter Aβ species without affecting Notch cleavage. However, two large Phase III studies in mild AD patients with tarenflurbil, a putative γ- secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New more selective γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks. Further understanding of the reasons of the failures of these γ-secretase-based drugs in AD may be important for the future research on effective treatments for this devastating disease.

Mitochondria play a key role in intracellular energy-generating processes, cell life and death, and are heavily involved in several metabolic pathways by integrating signaling networks; thus, a very large number of conditions are characterized by mitochondrial bioenergetic in humans. Often, mitochondrial changes are directly or indirectly dependent on the activation of intracellular stress cascades or death receptor-mediated pathways. Reactive oxygen species (ROS) formation, glutathione (GSH) depletion, protein alkylation and respiratory complex alterations are major events associated with mitochondrial dysfunction and represent critical initiating events in most forms of chronic liver disease. Through creating an analogy with a disrupted electric circuit gone bad, the present review focuses initially on how hepatic mitochondrial bioenergetics is affected in the context of drug and disease-induced liver failure and how targeting mitochondria with several antioxidant agents can be helpful for preventing the disruption of the mitochondrial electric circuit.

The influenza A virus is the main circulating influenza virus in the human population. It can cause disease also in birds and other mammals and is responsible for annual epidemics and occasional pandemics. The most known and deadly pandemic was the “Spanish flu” (influenza type A/H1N1), which struck the human population between 1918 and 1919, with probably the heaviest toll ever recorded in terms of human lives. The most recent flu pandemic, caused in 2009 by the swine-origin reassortant virus (pH1N1), has raised several critical issues in terms of our preparedness in responding fast to new pandemic influenza strains. Probably, the most instructive lesson that has been learned from the 2009 pandemic, was that the speed of manufacturing and distributing an effective vaccine will not be able to keep up with the pace of a rapidly spreading pandemic virus, failing to grant accessibility to the vaccine for a significant percentage of the susceptible population, before the onset of the pandemic peak. Thus, our first and most effective line of defense against a pandemic influenza virus, particularly in the early phases, are the antiviral drugs. Here we analyze our current understanding of the influenza pandemic viruses, in general, and of the pH1N1 in particular, along with the most recent approaches being pursued to design new anti-influenza drugs.

The Raf-MEK-ERK pathway is commonly activated in human cancers, largely attributable to the extracellular signal-regulated kinases (ERKs) being a common downstream target of growth factor receptors, Ras, and Raf. Elevation of these up-stream signals occurs frequently in a variety of malignancies and ERK kinases play critical roles in promoting cell proliferation. Therefore, inhibition of MEKmediated ERK activation is very appealing in cancer therapy. Consequently, numerous MEK inhibitors have been developed over the years. However, clinical trials have yet to produce overwhelming support for using MEK inhibitors in cancer therapy. Although complex reasons may have contributed to this outcome, an alternative possibility is that the MEK-ERK pathway may not solely provide proliferation signals to malignancies, the central scientific rationale in developing MEK inhibitors for cancer therapy. Recent developments may support this alternative possibility. Accumulating evidence now demonstrated that the MEK-ERK pathway contributes to the proper execution of cellular DNA damage response (DDR), a major pathway of tumor suppression. During DDR, the MEK-ERK pathway is commonly activated, which facilitates the proper activation of DDR checkpoints to prevent cell division. Inhibition of MEK-mediated ERK activation, therefore, compromises checkpoint activation. As a result, cells may continue to proliferate in the presence of DNA lesions, leading to the accumulation of mutations and thereby promoting tumorigenesis. Alternatively, reduction in checkpoint activation may prevent efficient repair of DNA damages, which may cause apoptosis or cell catastrophe, thereby enhancing chemotherapy's efficacy. This review summarizes our current understanding of the participation of the ERK kinases in DDR.