Current Medicinal Chemistry (v.22, #21)

Meet Our Editorial Board Member by Giovanni Davi (2505-2505).

Whilst knowledge of basic biology, diagnosis and prognosis of glioblastoma (GB – WHO grade IV) are steadily improving, advancements of therapy are discouragingly slow, with the only significant novelty during last ten years represented by introduction of temozolomide in chemotherapy. In order to analyze the current status of clinical research on GB, a literature search was conducted in PubMed using the terms: 'glioma AND trial' over a 500 day period elapsing from Jan 1, 2013 to May 15, 2014 and results of Phase I, II and III trials were reviewed. Results in the pediatric setting were included as well. It was concluded that, as in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field are not presently translated to improved patients' survival. In order to explore novel therapeutic avenues for this deadly tumour, two innovative medicinal chemistry approaches are proposed and discussed: a) Specific glioma initiating cell-radiosensitization by ATM inhibitors [1] and b) Specific glioma initiating cell-chemotherapeutic targeting by MYC inhibitors [2].

HER2-Mediated Anticancer Drug Delivery: Strategies to Prepare Targeting Ligands Highly Specific for the Receptor by Enrica Calce, Luca Monfregola, Michele Saviano, Stefania De Luca (2525-2538).
HER2 receptor, for its involvement in tumorigenesis, has been largely studied as topic in cancer research. In particular, the employment of trastuzumab (Herceptin), a humanized anti-HER2 antibody, showed several clinical benefits in the therapy against the breast cancer. Moreover, for its accessible extracellular domain, this receptor is considered an ideal target to deliver anticancer drugs for the receptormediated anticancer therapy. By now, monoclonal antibody and its fragments, affibody, and some peptides have been employed as targeting agents in order to deliver various drugs to HER2 positive tumor cells. In particular, the ability to perform a fast and reliable screening of a large number of peptide molecules would make possible the selection of highly specific compounds to the receptor target. In this regard, the availability of preparing a simplified synthetic model which is a good mimetic of the receptor target and can be used in a reliable screening method of ligands would be of a strategic importance for the development of selective HER2-targeting peptide molecules. Herein, we illustrate the importance of HER2-targeted anticancer therapies. We also report on a synthetic and effective mimetic of the receptor, which revealed to be a useful tool for the selection of specific HER2 ligands.

Nucleic Acid-Based Aptamers: Applications, Development and Clinical Trials by Jagat R. Kanwar, Kislay Roy, Nihal G. Maremanda, Krishnakumar Subramanian, Rakesh N. Veedu, Raj Bawa, Rupinder K. Kanwar (2539-2557).
Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with respect to their obvious advantages like high specificity and affinity, longer shelf-life, easier manufacturing protocol, freedom to introduce chemical modifications for further improvement, etc. Reiterative selection process of aptamers over 10-15 cycles starting from a large initial pool of random nucleotide sequences renders them with high binding affinity, thereby making them extremely specific for their targets. Aptamer-based detection systems are well investigated and likely to displace primitive detection systems. Aptamer chimeras (combination of aptamers with another aptamer or biomacromolecule or chemical moiety) have the potential activity of both the parent molecules, and thus hold the capability to perform diverse functions at the same time. Owing to their extremely high specificity and lack of immunogenicity or pathogenicity, a number of other aptamers have recently entered clinical trials and have garnered favorable attention from pharmaceutical companies. Promising results from the clinical trials provide new hope to change the conventional style of therapy. Aptamers have attained high therapeutic relevance in a short time as compared to synthetic drugs and/or other modes of therapy. This review follows the various trends in aptamer technology including production, selection, modifications and success in clinical fields. It focusses largely on the various applications of aptamers which mainly depend upon their selection procedures. The review also sheds light on various modifications and chimerizations that have been implemented in order to improve the stability and functioning of the aptamers, including introduction of locked nucleic acids (LNAs). The application of various aptamers in detection systems has been discussed elaborately in order to stress on their role as efficient diagnostic agents. The key aspect of this review is focused on success of aptamers on the basis of their performance in clinical trials for various diseases.

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations by Adam M. Curtin, Gemma K. Kinsella, John C. Stephens (2558-2579).
Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of biological processes, from vascular pressure to immune responses and neurological signalling cascades. Overproduction of NO has been implicated in conditions including Alzheimer's disease, Parkinson's disease and schizophrenia. Inhibition of nNOS therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These ligands have been targeted at four key binding sites of the nNOS enzyme - the tetrahydrobiopterin, calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the field of nNOS inhibition.

Non-Traditional Systemic Treatments for Diabetic Retinopathy: An Evidence-Based Review by Rafael Simo, Stefania Ballarini, Jose Cunha-Vaz, Linong Ji, Hermann Haller, Paul Zimmet, Tien Y Wong (2580-2589).
The rapid escalation in the global prevalence diabetes, with more than 30% being afflicted with diabetic retinopathy (DR), means it is likely that associated vision-threatening conditions will also rise substantially. This means that new therapeutic approaches need to be found that go beyond the current standards of diabetic care, and which are effective in the early stages of the disease. In recent decades several new pharmacological agents have been investigated for their effectiveness in preventing the appearance and progression of DR or in reversing DR; some with limited success while others appear promising. This up-to-date critical review of non-traditional systemic treatments for DR is based on the published evidence in MEDLINE spanning 1980-December 2014. It discusses a number of therapeutic options, paying particular attention to the mechanisms of action and the clinical evidence for the use of renin-angiotensin system blockade, fenofibrate and calcium dobesilate monohydrate in DR.

Antimicrobial resistance is one of the most serious public health problems. This is of particular concern when bacteria become resistant to various antimicrobial agents simultaneously and when they form biofilms. Consequently, therapeutic options for the treatment of infections have become limited, leading frequently to recurrent infections, treatment failure and increase of morbidity and mortality. Both, persistence and spread of antibiotic resistance, in combination with decreased effectiveness and increased toxicity of current antibiotics have emphasized the urgent need to search alternative sources of antimicrobial substances. Plants are recognized as a source of unexplored chemical structures with high therapeutic potential, including antimicrobial activity against clinically important microorganisms. Additionally, phytochemicals (plant secondary metabolites) present several advantages over synthetic molecules, including green status and different mechanisms of action from antibiotics which could help to overcome the resistance problem. In this study, an overview of the main classes of phytochemicals with antimicrobial properties and their mode of action is presented. A revision about the application of phytochemicals for biofilm prevention and control is also done. Moreover, the use of phytochemicals as scaffolds of new functional molecules to expand the antibiotics pipeline is reviewed.