Current Medicinal Chemistry - Volume 21, Issue 23, 2014

The polyglutamine (polyQ) diseases including Huntington’s disease and spinocerebellar ataxias are a group of inherited neurodegenerative diseases that are caused by an abnormal expansion of the polyQ stretch in disease-causative proteins. The expanded polyQ stretches are intrinsically unstable and are prone to form insoluble aggregates and inclusion bodies. Recent studies have revealed that the expanded polyQ proteins gain cytotoxicity during the aggregation process, which may possibly cause detrimental effects on a wide range of essential cellular functions leading to eventual neuronal degeneration. Based on the pathogenic mechanism of the polyQ diseases, several therapeutic approaches have been proposed to date. Among them, here we focus on peptide-based approaches that target either aggregate formation of the polyQ proteins or abnormal cellular processes induced by the expanded polyQ proteins. Although both approaches are effective in suppressing cytotoxicity of the abnormal polyQ proteins and the disease phenotypes of animal models, the former approach is more attractive since it targets the most upstream change occurring in the polyQ diseases, and is therefore expected to be effective against various downstream functional abnormalities in a broad range of polyQ diseases. One of the major current problems that must be overcome for development of peptide-based therapies of the polyQ diseases is the issue of brain delivery, which is also discussed in this article. We hope that in the near future effective therapies are developed, and bring hope to many patients suffering from the currently untreatable polyQ diseases.

Peptides have a great potential for the treatment of neurological disorders, but the clinical translation is still facing significant hurdles. Delivery issues are among them: for example the short systemic half-life of peptides, poor passage across the blood brain barrier, slow diffusion through the extracellular space and rapid cerebrospinal fluid washout. This review will discuss new findings on the blood brain barrier and the physiology of the cerebrospinal fluid system, which may be relevant for the delivery of peptides to the brain. It will also discuss delivery issues and opportunities related to different administration routes, i.e. intravenous, intraventricular and intracerebral. Lastly, we summarize stem cell-based approaches; such cell therapy relies on the secretion of soluble factors, i.e. peptides. We highlight approaches to use encapsulated, genetically engineered cells as a vehicle for sustained delivery of peptides to the diseased brain.

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in the laboratory of Prof. Illana Gozes. The effects of NAP and its related peptides in models of neurodegenerative diseases and other neurological disorders will be described here in details. Possible mechanisms of NAP actions include anti-inflammatory effect, antioxidant activity, inhibition of protein aggregation and interaction with microtubules. In line with the fact that all of these features are characteristic to most neurological/neurodegenerative disorders, NAP was found to have beneficial effects on the behavioral manifestations associated with these disorders.

The treatment of central nervous system (CNS) diseases is a major challenge. The presence of the barrier intended to protect the brain from unwanted molecules also impairs the efficacy of CNS-targeted drugs. The discovery of drug targets for CNS diseases opens a door for the selective treatment of these diseases. However, the physicochemical properties of drugs, including their hydrophilic properties and their peripheral metabolism, as well as the blood–brain barrier, can adversely affect the therapeutic potential of CNS-targeted drugs. Although peptides are often metabolized by enzymes, they are of particular interest for the treatment of CNS diseases or as carriers to deliver drugs to the brain. In this review, we discuss the use of peptides as potential prodrugs for the treatment of CNS diseases.

Neurodegenerative diseases are characterized by selective and progressive degeneration of neuronal population in the brain, and associated behavioural, motor, psychiatric and cognitive impairments. Aggregation of pathogenic proteins, mitochondrial dysfunction, oxidative stress, transcriptional dysfunction and apoptosis play an important role in the pathogenesis of neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Amyotrophic lateral sclerosis. Therefore, novel therapies that target each of these mechanisms may be effective in abating the symptoms and slow down the onset and progression of neurodegenerative disorders. This review offers insights into the tremendous utility and versatility of peptides such as neurotrophins, neurotrophic factors (NGF, BDNF and GDNF), neuropeptides, mitochondrial targeted antioxidants/peptides, MitoQ, neurturin, and β-sheet breaker peptides to address the mechanisms and pathogenesis associated with neurodegenerative disorders.

Protein-protein interactions are critical for cellular functioning, and their deregulation is involved in several diseases. Targeting these protein interacting domains could be a promising approach in drug designing. One such domain, the PDZ domain is encoded by several proteins of the nervous system in particular at the postsynaptic density site of neurons where they contribute to signal transduction pathways and neurotransmission. Since PDZ domains have well-defined binding sites, often corresponding to short amino acid motifs at the C-termini of target partner proteins, they provide promising targets for drug discovery. Viruses are art master in manipulating the signaling machinery of the cell they infect. Some of them such as rabies virus which promotes neuron survival by disrupting peculiar PDZ complexes can serve as a source of inspiration for the design of new neuroprotective drugs. This review highlights PDZ-mediated protein interactions in nervous system and their therapeutic potential.

Histone deacetylase inhibitors (HDACi) have been actively explored as anti-cancer agents due to their ability to prevent deacetylation of histones, resulting in uncoiling of chromatin and stimulation of a range of genes associated in the regulation of cell survival, proliferation, differentiation and apoptosis. During the past several years, many HDACi have entered pre-clinical or clinical research as anti-cancer agents with satisfying results. Out of these, more than 8 novel hydroxamic acid based HDACi i.e., belinostat, abexinostat, SB939, resminostat, givinostat, quisinostat, pentobinostat, CUDC-101 are in clinical trials and one of the drug vorinostat (SAHA) has been approved by US FDA for cutaneous Tcell lymphoma (CTCL). It is clear from the plethora of new molecules and the encouraging results from clinical trials that this class of HDAC inhibitors hold a great deal of promise for the treatment of a variety of cancers. In this review, we classified the hydroxamic acid based HDACi on the basis of their structural features into saturated, unsaturated, branched, un-branched and 5, 6-membered cyclic ring linker present between zinc binding group and connecting unit. The present article enlists reports on hydroxamic acid based HDACi designed and developed using concepts of medicinal chemistry, demonstrating that hydroxamate derivatives represent a versatile class of compounds leading to novel imaging and therapeutic agents. This article will also provide a complete insight into various structural modifications required for optimum anticancer activity.

In efforts to find agents with improved biological activity against cancer cells, recent years have seen an increased interest in the study of small molecules able to bind the deoxyribonucleic acid (DNA) when it assumes secondary structures known as G-quadruplexes (G4s) preferring them over the B form. Currently, several compounds reported in literature have already shown to be good candidates as G4s DNA stabilizers. Even though some specific features for the G4s affinity are known, such as a π-delocalized system able to stack at the top/end of a G-tetrad and positively charged substituents able to interact with the grooves, it is not clear yet what kind of structural features affect more the G4 arrangement. This is mainly due to the structure heterogeneity of both the G4 stabilizer compounds and the DNA G4s isoforms. In this review, we aim to classify some known G4 binders by analyzing them from a new perspective surprisingly never approached up to date: the symmetry features. Molecular symmetry could be responsible for the specific binding mode to the G4- DNA but could also be crucial in determining different isoform affinity. We propose to classify the G4s stabilizers in five main point group symmetry classes. This classification could be useful to design new ligands able to stabilize a specific G-quadruplex isoform, in order to increase the selectivity of new potential anticancer G-quadruplex targeting drugs, a goal yet highly sought by researchers.

Kinesin spindle protein (KSP) plays an essential role in centrosome separation and formation of the bipolar mitotic spindle. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new anticancer agents with reduced side effects relative to antimitotics that target tubulin. Small molecule KSP inhibitors have demonstrated their potential as novel antimitotic agents. Several KSP inhibitors have progressed into clinical trials and many others are in preclinical developments. Recently, KSP inhibitors of wide structural diversity have appeared in literatures. This review will summarize the developments of KSP inhibitors based on the five-membered heterocycle scaffolds in recent 10 years. These small molecule KSP inhibitors were classified as dihydropyrazoles, dihydropyrroles, thiophenes, dihydrothiadiazoles, thiazoles and fused pyrroles, their structure-activity relationships were discussed.

Apoptosis is a highly programmed cell death strictly connected to the pathogenesis of many human diseases, including neoplastic, neurodegenerative or cardiovascular diseases. Mitochondria play a key role in the apoptotic process; their damage activates a series of events which provoke the release of cytochrome c and other pro-apoptotic factors from the mitochondrial intermembrane space, and culminate in cell death. This review provides an overview of the key role played by mitochondria in the activation of the apoptotic process. In particular, the interest is focused on the role played by cardiolipin, a phospholipid deeply involved in the first steps of the process culminating in cell apoptosis. Mitochondrial phospholipids are involved in several cellular functions, such as cell respiration, apoptosis, and autophagy. Therefore, any alteration in the production of phospholipids or in their structural properties causes deep effects on the cell behavior and induces the arising of different pathologies. The present review summarizes the most recent advances in the study of the role that CL, a phospholipid possessing a unique structure, plays in mitochondrial activity, in apoptosis, and in the onset of human diseases.

Novel sulfa Schiff bases were synthesized and characterized by a reaction between aromatic sulfonamides and aromatic aldehydes or heterocyclic ketones in equimolar ratios. Their cytotoxicity was evaluated by the resazurin assay towards human sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Three of the tested compounds viz., 4-(anthracen-9-ylmethyleneamino)-N-(pyrimidin-2-yl)benzenesulfonamide (4), 4-(anthracen-9- ylmethyleneamino)benzenesulfonamide, (5) and 4-((3-phenylallylidene)amino)benzene-sulfonamide, (6) were cytotoxic (IC50 values: 5.38-19.96 μM). CEM/ADR5000 cells were not cross-resistant to these compounds, indicating activity against otherwise drug-resistant tumors. Compound 6 inhibited P-glycoprotein by increasing doxorubicin accumulation and reducing expression of P-glycoprotein in CEM/ADR5000 cells. A human P-glycoprotein homology model was used for molecular docking studies. Compound 6 and verapamil (a well-known P-glycoprotein inhibitor) docked with similar binding energies to the same binding pocket.