Current Drug Targets - Volume 16, Issue 10, 2015

The Eph receptors are the largest sub-family of Receptor Tyrosine Kinases (RTK). They, together with their ephrin ligands, play central roles in cell-cell communication during development, and also in the maintenance of a normal adult physiology. Their malfunction, therefore, can contribute to various human diseases. Since the structures of the Eph receptors and ephrins are by now well characterized, there has been extensive recent work to develop ways to manipulate their action in order to achieve therapeutic benefits. Although few reagents have progressed to clinical trials thus far, it is evident that the Eph receptors are valid targets for therapeutic drugs. In this review we first summarize studies on the three-dimensional structures of Eph receptors. We then give an overview on small molecule inhibitors and activators using Ephs as targets. We put a special focus on the latest developments in the field of monoclonal antibodies and antibody fragments for inhibiting or activating the Eph/ephrin signaling.

Eph receptor tyrosine kinases and ephrin ligands constitute an important cell communication system that controls development, tissue homeostasis and many pathological processes. Various Eph receptors/ephrins are present in essentially all cell types and their expression is often dysregulated by injury and disease. Thus, the 14 Eph receptors are attracting increasing attention as a major class of potential drug targets. In particular, agents that bind to the extracellular ephrin-binding pocket of these receptors show promise for medical applications. This pocket comprises a broad and shallow groove surrounded by several flexible loops, which makes peptides particularly suitable to target it with high affinity and selectivity. Accordingly, a number of peptides that bind to Eph receptors with micromolar affinity have been identified using phage display and other approaches. These peptides are generally antagonists that inhibit ephrin binding and Eph receptor/ ephrin signaling, but some are agonists mimicking ephrin-induced Eph receptor activation. Importantly, some of the peptides are exquisitely selective for single Eph receptors. Most identified peptides are linear, but recently the considerable advantages of cyclic scaffolds have been recognized, particularly in light of potential optimization towards drug leads. To date, peptide improvements have yielded derivatives with low nanomolar Eph receptor binding affinity, high resistance to plasma proteases and/or long in vivo half-life, exemplifying the merits of peptides for Eph receptor targeting. Besides their modulation of Eph receptor/ephrin function, peptides can also serve to deliver conjugated imaging and therapeutic agents or various types of nanoparticles to tumors and other diseased tissues presenting target Eph receptors.

Eph-ephrin system is emerging as a new potential target in several diseases including cancer, diabetes, neurodegenerative diseases and inflammation. In the last decade, several efforts have been made to develop small molecule antagonists of Eph receptors. Both natural and synthetic compounds were discovered with (poly) phenol and steroidal derivatives on one side and the α1 agonist doxazosin, 2,5-dimethylpyrrol- 1-yl-benzoic acids and amino acid conjugates of lithocholic acid on the other. In the present paper we critically present available data for these compounds and discuss their potential usefulness as pharmacological tools or as candidates for a lead-optimization program.

Lung cancer remains a leading cause of death. Current treatment options are generally ineffective, highlighting the dire need for novel approaches. While numerous biologically-active chemotherapeutics have been discovered in the last two decades, biological barriers including minimal water solubility, stability, and cellular resistance hinder in vivo effectiveness. To overcome these limitations, nanoparticles have been designed to deliver chemotherapeutics selectively to cancerous tissue while minimizing pharmacokinetics hindrance. Numerous studies are underway analyzing the efficacy of nanoparticles in drug delivery, theranostic applications, and photothermal therapy. However, while nanoparticles have shown efficacy in treating some cancers, their potential toxicity and lack of targeting may hinder clinical potential. With the aim to help sort through these issues, we conduct a review to describe recent applications of nanotherapeutics for the treatment and diagnosis of lung cancer. We first provide a detailed background of statistics, etiology, histological classification, staging, diagnosis, and current treatment options. This is followed by a description of current applications of nanotherapeutics, focusing primarily on results published during the past five years. The potential toxicity associated with nanoparticles is evaluated, revealing inconclusive information which highlights the need for further studies. Lastly, recent advances in mathematical modeling and computational simulation have shown potential in predicting tumor response to nanotherapeutics. Thus, although nanoparticles have shown promise in treating lung cancer, further multi-disciplinary studies to quantify optimal dosages and assess possible toxicity are still needed. To this end, nanotherapeutic options currently in clinical trials offer hope to help address some of these critical issues.

After the discovery of the db gene in 1966, it was determined that a blood-borne satiety factor was produced excessively, but was not responded to, in db/db mice. This model for type 2 diabetes is widely used since it phenocopies human disease and its co-morbidities including obesity, progressive deterioration in glucose tolerance, hypertension and hyperlipidaemia. Db/db mice, unlike their non-diabetic controls, have consistently elevated levels of liver glycogen, most likely due to hyperphagia. In transmission electron micrographs, liver glycogen usually shows a composite cauliflower-like morphology of large “α particles” (with a wide range of sizes) made up of smaller “β particles” bound together. New studies have explored the size distribution of liver glycogen molecules and found that α particles in db/db mice are more chemically fragile than those in healthy mice, and can readily break apart to smaller β particles. There is evidence that smaller glycogen particles have a higher association with glycogen phosphorylase, a key enzyme involved in glycogen degradation, as well as being degraded more rapidly in vitro; therefore the inability to form stable large glycogen α particles is predicted to result in a faster, less controlled degradation into glucose. The implications of this for glycaemic control remain to be fully elucidated. However, “rescuing” the more fragile diabetic glycogen to decrease hepatic glucose output in type 2 diabetes, may provide a potential therapeutic target which is the subject of this review.

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder that may develop after exposure to a life-threatening trauma. As veterans and armed forces may deal with diverse health problems compared with civilians, they have a greater risk for psychiatric disorders, including PTSD, than civilians, even if the disorder may be also frequent in the general population. PTSD is associated with significant comorbidity, especially with mood disorders and substance abuse. Moreover, the suicide risk is higher in PTSD patients than in the general population. Selective Serotonin Reuptake Inhibitors (SSRIs), atypical antipsychotics and benzodiazepines are commonly employed in the management of PTSD, but often these treatments fail or are discontinued due to adverse effects. It has been demonstrated that high noradrenergic activity may be associated with hyperarousal, trauma nightmares and sleep disturbances in PTSD subjects, probably through the stimulation of α -1 adrenergic receptors in the brain prefrontal cortex. The α -1 adrenoreceptor antagonist prazosin decreases noradrenaline effects at brain α-1 adrenoreceptors and may be a promising agent in the treatment of PTSD, as some studies have found it effective and well tolerated. Therefore, the present review is aimed to examine the role of noradrenergic system in the pathophysiology of PTSD. Moreover, we conducted a systematic review to evaluate the effectiveness and tolerability of prazosin in PTSD patients. Meta-analysis was used to combine data from multiple studies and better estimate the effect of prazosin on specific outcomes. We found prazosin to be significantly more efficacious than placebo in reducing distressing dreams in PTSD patients, even though our results should be interpreted with caution due to the small number of studies included in our quantitative synthesis.

Significant progress in the research of mammalian target of rapamycin (mTOR) in recent years, has greatly enhanced our understanding of the role and cellular pathways through which mTOR control cellular processes, such as translational initiation, actin organization, cell proliferation, and cell survival. mTOR is activated by phosphorylation and functions mainly through mTOR complex 1 or mTOR complex 2. mTORC1 is activated through tuberous sclerosis complex 1/2 dependent and independent mechanisms following the stimulation by growth factors, nutrient, amino acids, and other signaling pathways. The activity of mTOR is closely associated with cell proliferation and differentiation, apoptosis, and autophagy. Activation of mTOR prevents the induction of both apoptosis and autophagy through regulating its multiple targets. Given that the activity of mTOR has been involved in the pathogenesis of neurodegenerative disorders, cardiovascular abnormalities, metabolic diseases, renal transplantation, autoimmune abnormalities, and cancer, manipulating mTOR activation may represent as an innovative therapeutic strategy for these diseases. Yet, the role of mTOR in the body is complicated and therefore, its activity needs to be tightly regulated to achieve beneficial outcome in a specific pathological condition.

Plasmepsins, falcipains and aminopeptidases are Plasmodium falciparum proteases involved in human host hemoglobin degradation and other processes like erythrocyte invasion and rupture. Antimalarial drug resistance and natural selection in parasite are important reasons that create the urgent need of novel targets and lead compounds to overcome the burden of malaria. This report explored progress of the study covering proteases and their inhibitors specific to hemoglobin degradation. Additionally, in silico predicted antimalarial targets, balancing selection and drug-protein interaction are included.

Despite adequate surgery, women affected by advanced-stage gynaecological cancers (ovarian/ endometrial malignancies) carry an extremely poor prognosis; an improved oncological prognosis could largely depend upon the enhancement of adjuvant treatment. Recent data showed that, among women affected by endometrial/ovarian malignancies, a reduced cancer-related mortality was noted in statin-users compared to non-users, suggesting the need for clinical trials to define the anticancerproperties of statins. In vitro/in vivo evidences suggest a potential chemo-preventive effect through induction of cancer-cell apoptosis and inhibition of cancer-cell growth, proliferation, invasion, and metastasis. The potential oncological impact of this discovery compels us to investigate all possible molecular targets for anticancer activities of statins in order to identify a rationale in proposing their administration in association with standard chemotherapy/radiotherapy protocols after adequate surgical-treatment for advanced-stages gynaecological malignancies.