Mini Reviews in Medicinal Chemistry - Volume 10, Issue 7, 2010

After fifty years of DNA targeting through intercalators and groove binders and related studies now the current focus is in RNA targeting. Polyadenylic acid [poly(A)] tail of mRNA has been recently established as a potential drug target due to its significant role in the initiation of translation, maturation and stability of mRNA as well as in the production of alternate proteins in eukaryotic cells. Isoquinoline group of alkaloids have their importance in contemporary biomedical research and drug discovery programme due to extensive pharmacological and biological activity. Very recently some small molecule alkaloids of the isoquinoline group have been found to bind poly(A) with remarkably high affinity leading to self structure formation. These alkaloids have a high binding affinity towards single stranded poly(A) whereas their binding with double stranded poly(A) is weak. Among the alkaloids discussed here, berberine and coralyne are found to be capable inducing self-structure in poly(A). All the binding phenomena are characterized by electrostatic interaction between RNA and the alkaloids and the mode of binding was revealed as either as full or partial intercalation. This review focuses on the structural and biological significance of poly(A) and the recent developments in the use of plant alkaloids and their synthetic analogs to control the structure and function of this RNA for the development of new alkaloid based molecules specifically targeted to poly(A) structures.

RNA interference technology has become a powerful laboratory tool to study gene function. Small interfering RNAs (siRNAs) have provided unprecedented opportunities for the development of new therapeutics in human diseases. Unfortunately, siRNA duplexes are not optimal drug-like molecules. The problems for their effective application are fundamentally delivery, stability and off-target effects. Chemical modification provides solutions to many of the challenges facing siRNA therapeutics. In this review, we recapitulate and discuss the development of the latest described chemical modifications of siRNAs, with a special focus on novel chemical modifications of siRNA structure, architecture and siRNA conjugates.

Host defence peptides (HDPs) are multi-functional inducers and effectors of host immunity. Through their direct antimicrobial activity HDPs have for been successfully utilized for many years as topical antibiotics and food preservatives. The more recent appreciation of HDP immunomodulatory activities offers additional opportunities for application as systemic antimicrobials, anti-inflammatory agents and vaccine adjuvants. HDPs have demonstrated proof-ofprinciple success in each of these applications. Optimization of HDPs for these objectives will benefit from a greater comprehension of the structural basis of their various activities. Such an understanding will facilitate rational design and/or selection of peptides with enhanced properties. This is complicated, however, by the diversity of HDP sequences, structures and mechanisms of action. Furthermore, while the ability of HDPs to undergo template-driven formation of bioactive structures enables these small peptides to perform a diverse range of actions it also complicates efforts to understand contributions of particular structural features to specific activities. With recognition of these limitations, but consideration of the emerging importance of this exciting class of molecules, we review the current understanding of the structural basis of select HDP activities as well as present strategies for HDP selection and optimization.

Sesquiterpene lactones of the guaianolide and eudermanolide types are considered of interest because they have an effect in the regulation and prevention of oxidative damage and inflammation-mediated biological damage. Dehydroleucodine, a natural sesquiterpene isolated from Artemisia douglasiana Besser, and ilicic aldehyde, a semi-synthetic sesquiterpene lactones, showed in vivo protection in ethanol-induced gastric mucosa damage. This action was determined by in situ gastric mucosa chemiluminescence and by tissue antioxidant content.

Although a relatively rare malignancy with a national incidence of 3500-4000 annually, Gastrointestinal Stromal Tumor (GIST) is of significance in the realm of clinical and pharmacological research. GIST exhibits remarkable uniformity in its pathogenesis and ultrastructure as 95% of cases are linked to constitutive activation and overexpression of a membrane tyrosine kinase, c-KIT (CD117). Although previously refractory to any course of action but surgery, GIST heralded a triumph in targeted cancer therapy when administration of a specific first-generation tyrosine-kinase inhibitor Imatinib mesylate (STI571) was shown to inhibit c-Kit and demonstrated a significant increase in patient survival. Over the subsequent decade, GIST has become a paradigm for the potency of Imatinib in adjuvant or neoadjuvant therapy, showcasing the clinical relevance and rapidity of translational research in the field of targeted molecular therapy. Subsequent to demonstrating the efficacy of Imatinib as a therapeutic agent, GIST has also exposed the limitations of current targeted therapies. Within two years, 50% of GISTs develop secondary mutations that allow resistance to Imatinib. However, extensive research regarding both primary and secondary c-KIT mutations has illuminated the mechanisms of Imatinib resistance and has the potential to ameliorate this therapeutic setback. Current research to this end lies in two primary directions: the development of tyrosine kinase inhibitors (some of which also inhibit other oncongenic agents such as PDGFR, bcr-abl, and VEGF) that are either generally more potent than Imatinib or less susceptible to specific mechanisms of resistance; and drugs that target the downstream effectors of the mutant c-KIT kinase, including PKC and mTOR. This paper will systematically review current research on second-generation targeted molecular therapy in the treatment of GIST, and expand upon its value as a model for treatment of other solid organ tumors.

Kv1.5 channels are homotetramers of α-pore subunits mainly present in human atrium and pulmonary vasculature. Thus, Kv1.5 is a pharmacological target for cardiovascular diseases. Kvβ1.3 assemblies with Kvα1.5 and modifies its gating and pharmacology. A further knowledge of α-β interactions and pharmacology will lead a better design of new drugs.

Species of the genus Iris (Iridaceae) have a long history of traditional medicinal use in many places of the world, and they have been previously recognized as rich sources of secondary metabolites, in which flavonoids are found predominantly. During the last decade (1999-2008) over 90 flavonoid constituents have been discovered and characterized, including 38 new compounds, from 15 species of Iris. This review elucidates the structural features of these flavonoid constituents, and gives the details of their source, identification, biological activity and chemotaxonomy significance. At last, a checklist of the flavonoid compounds in Iris by species is given.