Current Medicinal Chemistry - Volume 22, Issue 8, 2015

The cysteine protease family members play important roles in various pivotal cellular processes. The difficulty in the analysis of the effects of cysteine protease aberrations in cancer comes as a result of the fact that they take part in complex proteolytic pathways. Nevertheless, there is a vast amount of data regarding the involvement of distinct members of this family in divergent types of cancer. Cysteine proteases assist migration and development of the disease, as well as increase the invasiveness of particular kinds of tumors. They are designated as both drug targets, as well as cancer susceptibility biomarkers. This implies that the abnormalities in their activity and expression patterns may be associated with the hallmarks of cancer. This review demonstrates that the influence of cysteine proteases on different mechanisms underlying cancer is undisputable. Thus, they are potent targets for future study and should be recognized as key players in the fight against cancer.

Tumor microenvironment can differ considerably in various types of tumors in terms of cellular and cytokine networks and molecular drivers. The well known link between inflammation and cancer has recently found a number of genetic and molecular confirmations. In this respect, numerous reports have revealed that infection and chronic inflammation can contribute to cancer development, progression and control. Adhesion molecules, chemokines and proinflammatory cytokines, that enroll leukocytes, are persistently present in cancer microenvironment, thus increasing the risk for developing tumors. In this respect, cancer-derived microvescicles, in particular exosomes, exert an important role in the recruitment and reprogramming of components of tumor microenvironment. The relationship between cancer and virus infection has generated, in recent years, a great interest for studies aiming to better understand the role of the immune system in the control of these infections and of the immune cofactors in the promotion of the virus-induced neoplastic transformation. This suggests that virus-induced immune alterations may play a role to create an immunotolerogenic microenvironment during the carcinogenesis process.

The current pharmacological therapies for the treatment of Parkinson’s disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson’s disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson’s disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson’s disease.

Sigma-2 receptor is a widely distributed protein, which can modulate cell proliferation and involved in the pathogenesis of tumor. Photoaffinity labelling techniques testified that its molecular size is about 18 kDa. Recent studies indicated that sigma-2 receptor modulates the cytosolic Ca2+ concentration, dopaminergic transmission, and cocaine-induced addiction behavior. Some sigma-2 receptor ligands (ditolylguanidine, afobazole, etc) display the neuroprotective effect. Although sigma-2 receptor hasn’t been cloned, tens of sigma-2 receptor ligands, which demonstrate high affinity and selectivity, have been identified in the past decade. In this review, we mainly focus on these series of selective sigma-2 receptor ligands, their neuropsychological effects, and molecular probes for tracing sigma-2 receptors in central nervous system.

Dementia is a strongly age-related syndrome due to cognitive decline that can be considered a typical example of the combination of physiological and pathological aging-associated changes occurring in old people; it ranges from intact cognition to mild cognitive impairment, which is an intermediate stage of cognitive deterioration, and dementia. The spread of this syndrome has induced to study and try to reduce dementia modifiable risk factors. They include insulin resistance and hyperinsulinaemia, high blood pressure, obesity, smoking, depression, cognitive inactivity or low educational attainment as well as physical inactivity and incorrect diet, which can be considered one of the most important factors. One emerging strategy to decrease the prevalence of mild cognitive impairment and dementia may be the use of nutritional interventions. In the last decade, prospective data have suggested that high fruit and vegetable intakes are related to improved cognitive functions and reduced risks of developing a neurodegenerative process. The protective effects against neurodegeneration could be in part due to the intake of flavonoids that have been associated with several health benefits such as antioxidant and anti-inflammatory activities, increased neuronal signaling, and improved metabolic functions. The present article is aimed at reviewing scientific studies that show the protective effects of flavonoid intake against mild cognitive impairment and dementia.

Over the past few years, use of the genome-wide association study (GWAS) has made it possible to identify the primary genetic mechanisms of essential hypertension. GWAS results have helped identify many loci in or near genes that generally were not expected to be associated with blood pressure or essential hypertension. However, considering the great expectations of improving clinical outcomes and the billions of dollars that have been spent on various GWASs, the progress made so far has been slow. There are several factors that could be responsible for the relative lack of success of GWASs. First, it is possible that the number of people enrolled in the various GWASs was not enough, thereby limiting the power to detect additional markers. Second, although the alleles that are associated with a modest increase in risk are constantly being found, their discriminatory ability and use as predictive markers has been quite low. Difficulties with control group selection along with unrepeatability have also been problematic when using GWASs. The current paper summarizes the recent progress attained when using a GWAS of hypertension to identify the many loci associated with essential hypertension. In this review, we discuss the progress and issues of a GWAS for hypertension.

Despite progress in pharmacological modalities, treatments for ocular diseases are inconvenient, traumatic, costly and often end in poor final visual results. Peptides, considered as protein fragments, can adequately mimic protein binding and thus are used as therapeutic agents. Chemical modifications and bioengineering techniques are being frequently introduced to improve efficacy and stability of peptides, thereby improving their druggability. Cell-penetrating peptides (CPPs), peptides characterized by penetrating plasma membrane, are famous barrier- passers. They are good candidates for carrying drugs through ocular barriers. Therapeutic peptide and CPP perfectly complement each other. Once united, they may form an optimal formula for ocular topical administration, which can work both effectively and smartly. The consequent noninvasive delivery and economical cost would actualize prophylactic intervention, early treatment and long-term therapy to avoid chronic irreversible vision loss. The aim of the current review is a) to summarize recent therapeutic peptides, both anti-angiogenic and anti-inflammation, evidenced by animal experiments in vivo; b) to discuss the discovery strategies for therapeutic peptide; c) to present current delivery strategies for ophthalmic therapeutic peptide; and d) to introduce CPPs which are capable to deliver cargos to intraocular space via ocular surface administration.

In the search of novel enzyme-based prodrug approaches to improve pharmacological properties of therapeutic drugs such as solubility and bioavailability, dipeptidyl-peptidase IV (DPP IV, also termed as CD26) enzyme activity provides a previously unexplored successful prodrug strategy. This review covers key aspects of the enzyme useful for the design of CD26-directed prodrugs. The proof-of-concept of this prodrug technology is provided for amine-containing agents by directly linking appropriate di- (or oligo)peptide moieties to a free amino group of a non-peptidic drug through an amide bond which is specifically hydrolized by DPP IV/CD26. Special emphasis is also made in discussing the design and synthesis of more elaborated tripartite prodrug systems, for further extension of the strategy to hydroxy-containing drugs. The application of this technology to improve water solubility and oral bioavailability of prominent examples of antiviral nucleosides is highlighted.