Current Drug Targets (v.15, #7)

Phosphorothioate Oligonucleotides: Effectiveness and Toxicity by Tommaso Iannitti, Julio Cesar Morales-Medina, Beniamino Palmieri (663-673).
Background: Many experimental and clinical studies have focused on the antisense strategy. In this contextphosphorothioate oligonucleotides are compounds addressed to hybridize to a targeted mRNA inducing a variety of effectsincluding inhibition of the expression of proteins involved in different pathological processes and preventingtranslation. Methods: In this review, we provide an update on clinical efficacy and toxicological profile of phosphorothioateoligonucleotides used in experimental and clinical studies, also focusing on the use of the antisense strategyin the context of Duchenne muscular dystrophy which is a key pathology to study different aspects of this therapy.Pubmed/Medline was searched using the keyword “Phosphorotioate” combined with “Antisense”, “Oligonucleotide”and “Duchenne muscular dystrophy”. Conclusions: Phosphorothioate oligonucleotide transient activation of the complementcascade represents the most evident toxicological response, as showed by in vivo studies. It is also known thatmany of these compounds induce a prolongation of activated partial thromboplastin time, a reaction which is oftenhighly transient and proportional to the oligonucleotide plasma concentrations, making that effect clinically insignificantfor the current treatment regimens. In summary, current evidence shows limited untoward effects and reversibilityof the damage induced, at least for some of those compounds, with promising effectiveness for treatment of various pathologies.

IGF-1R, an important member of the IGF signaling system, is a plasma-membrane-bound receptor composedof two α -subunits and two β-subunits. IGF-1R has been revealed to play a pivotal role in cancer cell proliferation, differentiation,apoptosis and phenotype transformation, resulting uncontrolled tumor-cell growth. During the last decades,IGF-1R monoclonal antibody combined with chemotherapeutic agents as a novel cancer treatment approach has shownsynergistic effect in cancer treatment in some preclinical and clinical trials. Prolonged progression-free survival rate, objectiveresponse rate and stable disease were shown in some sorts of cancer patients compared to those implemented traditionalstandard chemotherapy. However, not all related clinical trials demonstrated expected promising outcomes. Mosttreatment-related adverse events in those studies are mild and manageable. The most frequently happened side effect ishyperglycemia in majorities of combined cancer therapy studies. Herein, we summarized the recent online and publishedliteratures concerning the safety, tolerability, anti-tumor activity and adverse events of this novel strategy. Besides, thiswork attempts to provide convincible evidence to warrant further investigation to identify prognostic biomarkers on neoplasm.

Fused Aryl-Phenazines: Scaffold for the Development of Bioactive Molecules by N.S. Hari Narayana Moorthy, Vijayakumari Pratheepa, Maria J. Ramos, Vitor Vasconcelos, Pedro A. Fernandes (681-688).
Fused aryl phenazine derivatives (benzo[a]phenazine, pyrido[a]phenazine, benzo[a]phenazine diones, tetrahydropyrido[a]phenazine (dermacozines), etc) are important heterocyclic compounds, which exhibit various pharmacologicalactivities, prominently in cancer cell lines. These compounds significantly intercalate between DNA base pairs and inhibitthe activities of topoisomerase I and II enzymes (Topo I and II). XR11576, XR5944, NC-190 and NC-182 belong tophenazine/fused aryl phenazine category and are under clinical studies. Several fused aryl phenazine dione compoundssuch as pyridazino[4,5-b]phenazine-5,12-diones, 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-diones, 6,11-dihydrobenzo[2,3-b]phenazine-6,11-diones, tetrahydropyrido[a]phenazine, etc possessed anticancer activities on various cancercell lines. Benzo[a]phenazine diimine and various other fused aryl phenazine compounds form coordination complex withthe metal ions (Ru, Rh, Zn and Pt) that intercalate with the DNA and are used for the treatment of cancer. These moleculeshave influence on MDR cancer cells and serve as anticancer agents in MDR cancer cells. The structure activity relationshipof the fused aryl phenazine derivatives revealed that the occurrence of four or more nitrogen atoms in the compoundshas better anticancer activity than those molecules with less number of nitrogen atoms. Phenazine antibiotics derivedfrom marine microbes are used for the treatment of microbial and worm diseases. Recent patents on these scaffoldsshowed that the benzo[a]phenazine derivatives have inhibitory activity on topoisomerase enzymes (Topo I and II) and thatact as anticancer agents.

The overuse of antibiotics which exerts the selective pressure for bacterial pathogens has facilitated the spreadof antibiotics' resistance. Metallo-β-lactamases (Mβ Ls) are zinc enzymes produced by an increasing number of bacterialpathogens. They can readily cleave carbapenems and most other β-lactams that are mainstays of therapy for bacterial infections.Mβ L-conferred resistance to antibiotics is most worrisome due to M β Ls exhibiting very broad-spectrum resistance.Therefore, the bacteria carrying Mβ Ls have recently become a significant clinical threat. No clinically useful M β Lsinhibitor has been discovered yet. To address the serious threat to public health posed by the Mβ L-conferred resistance toantibiotics, novel effective M β L inhibitors are urgently needed. This review mainly describes various M β L inhibitors, givingspecial attention to their antibacterial activity, mechanisms of action, structure-activity relationships and synergetic effectwith clinically available antibiotics.

Beneficial Effects of Selective Vitamin D Receptor Activation by Paricalcitol in Chronic Kidney Disease by Javier Donate-Correa, Virginia Domínguez-Pimentel, Mercedes Muros-de-Fuentes, Carmen Mora-Fernández, Ernesto Martín-Nunez, Violeta Cazana-Perez, Juan F. Navarro-González (703-709).
In chronic kidney disease patients, active vitamin D level progressively declines in the course of the disease.This phenomenon is accompanied by elevation of parathyroid hormone, resulting in secondary hyperparathyroidism(SHPT), increased phosphorus levels, and hypocalcemia. All these disorders are associated with high rates of cardiovascularmorbidity and mortality in these patients. Many vitamin D analogs have been approved for the treatment of SHPT inrenal patients. Currently, new and more selective vitamin D receptor activators (VDRAs) have been introduced in thistherapy with the aim of reducing SHPT without the hypercalcemia and hyperphosphatemia associated with the use of nonselectiveVDRAs. In addition, amelioration in hypertension, albuminuria, insulin resistance, and inflammation have beensuggested as consequences of vitamin D receptor (VDR) activation. In this work, we summarize the beneficial effects attributedto paricalcitol, the only selective, new generation VDRA, currently available in Europe and the USA, with provenefficacy in the control of SHPT both in hemodialysis (HD) and pre-dialysis patients. Paricalcitol exerts less calcemic andphosphatemic effects than other VDRAs and prevents deleterious bone resorption. Moreover, paricalcitol-based therapyhas been related to beneficial effects that could favor survival rates in chronic kidney disease patients. These benefits includeanti-inflammatory and antithrombotic effects, the inhibition of vascular smooth muscle cell proliferation, the reninangiotensinsystem, vascular calcification, and regression of left ventricular hypertrophy, which could reduce the risk ofcardiovascular mortality.

Mitochondrial Pathology in Osteoarthritic Chondrocytes by Longhuo Wu, Haiqing Liu, Linfu Li, Hai Liu, Qilai Cheng, Hongliang Li, Hao Huang (710-719).
Osteoarthritis (OA) is a chronic degenerative disease leading to aberrance of cartilage structures with unclear ormultifactorial mechanisms. Recently, a great portion of research endeavor to explore the molecular mechanisms of OA infocusing on the mitochondrial pathology. Mitochondrial respiratory chain (MRC) produces reactive oxygen species(ROS), which in turn impair mtDNA integrity and link to cartilage degradation in OA. The fine-tuning between ROS andantioxidant within chondrocytes ensures cartilage homeostasis. With disturbance from pro-inflammatory cytokines, oxidativestress synergistically instigates cellular signaling and exacerbates mitochondrial pathology, which may affect severalpathways implicated in OA cartilage degradation, including oxidative stress, increase of cytokine-induced chondrocytesinflammation and matrix catabolism, aging and senescence, obesity-related pathology, and cartilage matrix calcification.Unveiling the molecular mechanisms of mitochondrial function in OA pathogenesis and progression is essential for providingrelevant therapeutic targets. These suggest that efficient protection and improvement of mitochondrial activity canbe a therapeutic alternative for OA patients.

The Role of P2Y12 Receptor and Activated Platelets During Inflammation by Elisabetta Liverani, Laurie E. Kilpatrick, Alexander Y. Tsygankov, Satya P. Kunapuli (720-728).
Platelets play an important role not only during thrombosis, but also in modulating immune responses throughtheir interaction with immune cells and by releasing inflammatory mediators upon activation. The P2Y12 receptor is a Gicoupledreceptor that not only regulates ADP-induced aggregation but can also dramatically potentiate secretion, whenplatelets are activated by other stimuli. Considering the importance of P2Y12 receptor in platelet function, a class of antiplateletdrugs, thienopyridines, have been designed and successfully used to prevent thrombosis. This review will focus onthe role of activated platelets in inflammation and the effects that P2Y12 antagonism exerts on the inflammatory process. Achange in platelet functions was noted in patients treated with thienopyridines during inflammatory conditions, suggestingthat platelets may modulate the inflammatory response. Further experiments in a variety of animal models of diseases,such as sepsis, rheumatoid arthritis, myocardial infarction, pancreatitis and pulmonary inflammation have alsodemonstrated that activated platelets influence the inflammatory state. Platelets can secrete inflammatory modulators in aP2Y12-dependent manner, and, as a result, directly alter the inflammatory response. P2Y12 receptor may also be expressedin other cells of the immune system, indicating that thienopyridines could directly influence the immune system ratherthan only through platelets. Overall the results obtained to date strongly support the notion that activated plateletssignificantly contribute to the inflammatory process and that antagonizing P2Y12 receptor can influence the immuneresponse.

Supramolecular Chiro-Biomedical Aspect of β-Blockers in Drug Development by Imran Ali, Ashanul Haque, Mohamed F. Al Ajmi, Afzal Hussain, Mohd Marsin Sanagi, Iqbal Hussain, Hassan Y. Aboul-Enein (729-741).
β-Blockers are used globally for the treatment of cardiovascular problems. Unfortunately, these are consumedas racemic mixture causing serious side effects due to the presence of unwanted enantiomers. A simulation study of somecommonly used β-blockers was carried out at supramolecular level to understand stereo-selective binding of β -blockerswith receptors (β -ARs). The values of docking energy ranged from 6.58 to 9.11 and 7.05 to 9.15 kcal/mol for R- andS-enantiomers, respectively. Mostly, S-enantiomers bind stronger with β-ARs (in terms of docking energy) than their Rantipodes,with some exceptions. The results of docking study indicated higher pharmaceutical potencies of S-enantiomersthan R-antipodes.