Current Medicinal Chemistry (v.20, #29)

MicroRNAs and Cancer Therapy ? From Bystanders to Major Players by Cornelia Braicu, George A. Calin, Ioana Berindan-Neagoe (3561-3573).
MicroRNAs (miRNAs) are an evolutionarily conserved class of small regulatory RNAs that modulate gene expression.Extensive research over the last decade has shown that miRNAs are master regulators of cellular processes, withan essential role in cancer initiation, progression, and metastasis. Widespread deregulation of miRNAs in cancers hasidentified oncogenic and tumor-suppressive roles for these miRNAs. On the basis of these observations, miRNAs haveemerged as promising therapeutic tools for cancer management. In this review, we focus on the roles of miRNAs in tumorigenesis,the rationale and strategies for the use of miRNA-based therapy for cancer, and the advantages and currentchallenges to their use.

Potential MicroRNA Targets for Cancer Chemotherapy by Subee Tan, Yihan Wu, Chen-yu Zhang, Jinbo Li (3574-3581).
MicroRNA (miRNA) is an important type of non-coding RNAs with both physiological and pathological functionsin human beings. Aberrant expression of miRNAs has been found in tumor tissues and the expression profile of certaingroups of miRNAs is now emerging as bio-marker for cancer. It has been confirmed that miRNAs can exert oncogenicor tumor-suppressive functions through repressing the expression of their target genes which play different roles intumorigenesis. The identification of oncogenic or tumor-suppressive miRNAs allows potential applications of these miRNAsas targets for cancer chemotherapy. In this review, we summarized the well-known cancer-related miRNAs reportedin recent years and the roles they played in tumorigenesis and progression by targeting specific genes. Strategies developedto modulate the function or expression of the dysregulated miRNAs are also reviewed with recent examples illustratingtheir potential applications in cancer chemotherapy.

Canonical and Non-Canonical Barriers Facing AntimiR Cancer Therapeutics by Christopher J. Cheng, W. Mark Saltzman, Frank J. Slack (3582-3593).
Once considered genetic ?oddities?, microRNAs (miRNAs) are now recognized as key epigenetic regulators ofnumerous biological processes, including some with a causal link to the pathogenesis, maintenance, and treatment of cancer.The crux of small RNA-based therapeutics lies in the antagonism of potent cellular targets; the main shortcoming ofthe field in general, lies in ineffective delivery. Inhibition of oncogenic miRNAs is a relatively nascent therapeutic concept,but as with predecessor RNA-based therapies, success hinges on delivery efficacy. This review will describes the canonical(e.g. pharmacokinetics and clearance, cellular uptake, endosome escape, etc.) and non-canonical (e.g. spatial localizationand accessibility of miRNA, technical limitations of miRNA inhibition, off-target impacts, etc.) challenges tothe delivery of antisense-based anti-miRNA therapeutics (i.e. antimiRs) for the treatment of cancer. Emphasis will beplaced on how the current leading antimiR platforms?ranging from naked chemically modified oligonucleotides tonanoscale delivery vehicles?are affected by and overcome these barriers. The perplexity of antimiR delivery presentsboth engineering and biological hurdles that must be overcome in order to capitalize on the extensive pharmacologicalbenefits of antagonizing tumor-associated miRNAs.

MicroRNAs (miRNAs) are single-stranded non-coding RNAs of ~22 nucleotides, which can negatively regulategene expression through induction of mRNA degradation and/or post-transcriptional gene silencing. MiRNAs are keyfactors in the regulation of many biological processes such as cell proliferation, differentiation, and death. Since miRNAsare known to be in close association with cancer development, non-invasive imaging of miRNA expression and/or activityis of critical importance, for which conventional molecular biology techniques are not suitable or applicable. Over the lastseveral years, various molecular imaging techniques have been investigated for imaging of miRNAs. In this review article,we summarize the current state-of-the-art imaging of miRNAs, which are typically based on fluorescent proteins, bioluminescentenzymes, molecular beacons, and/or various nanoparticles. Non-invasive imaging of miRNA expressionand/or biological activity is still at its infancy. Future research on more clinically relevant, non-toxic techniques is requiredto move the field of miRNA imaging into clinical applications. Non-invasive imaging of miRNA is an invaluablemethod that can not only significantly advance our understandings of a wide range of human diseases, but also lead tonew and more effective treatment strategies for these diseases.

Small Molecules Modulating Biogenesis or Processing of microRNAs with Therapeutic Potentials by J. Li, W. Zhang, M. Zhou, R. Kooger, Y. Zhang (3604-3612).
MicroRNAs (miRNAs) are single-stranded non-coding RNAs with the ability to regulate gene expression atpost-transcriptional level. Typically, miRNAs function by binding to the 3? untranslated regions (UTR) of target mRNAs,leading to the degradation or repressed expression of target genes. It is estimated that miRNAs are involved in almostevery genetic pathway and the regulation of miRNAs plays important roles in physiological and pathological processes.Small molecules that can regulate miRNAs have great potential as probes to explore miRNAs-mediated regulatory network.Small-molecule regulators of disease-related miRNAs also hold the potential as novel therapeutic agents. Based onthe screening systems developed in recent years, several small-molecule regulators have been identified as specific or universalregulators of miRNAs. Therapeutic potentials of these small molecules have also been demonstrated. A general reviewon the reported small molecules modulating the biogenesis or function of miRNAs will be presented in this paper,with emphasis on the screening methods, proposed mechanism of action and the therapeutic potentials of these smallmolecules.

Roles of miRNA in Cardiovascular Development and Dysfunction by W. Huang, Q. Yu, Q. Wang, F. Cao (3613-3622).
Non-coding RNAs, especially microRNAs (miRNAs), have been recently found to play a major role in thepost-transcriptional regulation of both development and dysfunction of the cardiovascular system. Mechanistically, the inductionor repression of miRNAs occurring in cardiovascular dysfunction triggers downstream cardiac events in a celltype-specific manner. More importantly, the endogenous microRNAs? disturbance can be modified to rescue cardiac functionthrough exogenous overexpressing or neutralizing strategy. In this paper, we summarizes the current knowledgeabout miRNAs functions as well as their role in cardiac development and disease, and reports novel miRNAs-based therapeuticapproaches to counteract maladaptive remodeling upon cardiac dysfunction.

MicroRNAs are small non-coding RNA transcripts that modulate gene expression and translation through targetmRNA destabilization and/or inhibition of protein synthesis. Various studies have aimed at elucidation of the role ofthese small molecules in the regulation of disease activity. Initially, microRNA were believed to merely act as intracellularmediators fine-tuning mRNA translation into proteins. Recently, the first studies have emerged demonstrating that microRNAsare also externalized from cells and transported in body fluids, thereby shuttling genetic information from a donorto a recipient cell. Thus, circulating microRNAs represent attractive non-invasive detectable markers to monitor onset/progress of diseases. The present article outlines the quantification and biomarker use of microRNAs in various bodyfluids of patients with cardiac and kidney disease as well as neurological disorders.

The most abundant microRNA (miRNA) in the liver, miR-122, is regulated by specific, liver-enriched transcriptionfactors and is responsible for proper proliferation and differentiation of hepatocytes and for the regulation oflipid and cholesterol metabolisms. miR-122 is also involved in several hepatic disorders, as downregulation of miR-122 isoften associated with hepatocellular carcinoma (HCC) and miR-122 is a required component for the replication and proliferationof the hepatitis C virus (HCV). Various probes have been developed to promote a better understanding of the involvementof miR-122 in liver diseases, including modified antisense agents and small molecule inhibitors. These agents,capable of specifically modifying miR-122 activity, provide excellent tools to investigate the function and regulation ofmiR-122 and offer potential new lead compounds for drug discovery. Especially small molecule modifiers can displaynumerous advantages over nucleotide analogs, as discussed in this review.

Advances in Chemical Synthesis of Structurally Modified Bioactive RNAs by Ziyuan Li, Haipin Zhou, Xiaoming Wu, Hequan Yao (3641-3654).
Methods for the chemical synthesis of RNA have been available for almost half century, and presently, RNAcould be chemically synthesized by automated synthesizers, using protected ribonucleosides preactivated as phosphoramidites,which has already been covered by many reviews. In addition to advancement on synthetic methods, a variety ofmodifications have also been made on the synthesized oligonucleotides, and previous reviews on the general synthesis ofRNAs have not covered this area. In this tutorial review, three types of modifications have been summarized standing atthe viewpoint of medicinal chemistry: (1) modifications on nucleobase, comprising substituent introduction and replacementwith pseudobase; (2) modifications on ribose, consisting of modifications on the 2’, 3’ or 5’-position, alternation ofconfiguration, and conformational restriction on ribose; (3) modifications on internucleoside linkages, including amide,formacetal, sulfide, sulfone, ether, phosphorothiolate and phosphorothioate linkages. Synthetic methods achieving thesemodifications along with the functions or values of these modifications have also been discussed and commented on.

Development of RNA Aptamer-Based Therapeutic Agents by Y. Li, H. Wu, Y. Niu, Y. Hu, Q. Li, C. Cao, J. Cai (3655-3663).
RNA aptamers are non-coding small RNAs that bind to their cognate targets with high specificity and affinity.They are generally identified by iterative rounds of in vitro selection termed SELEX (Systemic Evolution of Ligands byExponential Enrichment). Similar to antibodies, they can inhibit, modulate and disrupt the functions of target proteins effectively,making them promising therapeutic agents for the treatment of various diseases and targeted drug delivery.Herein we summarize the recent progress of RNA aptamers as potential therapeutics, and highlight a few pioneer examplesin the stage of both clinical trials and pre-clinical developments.

Multimodality Imaging of RNA Interference by T. R. Nayak, L. K. Krasteva, W. Cai (3664-3675).
The discovery of small interfering RNAs (siRNAs) and their potential to knock down virtually any gene of interesthas ushered in a new era of RNA interference (RNAi). Clinical use of RNAi faces severe limitations due to inefficiencydelivery of siRNA or short hairpin RNA (shRNA). Many molecular imaging techniques have been adopted inRNAi-related research for evaluation of siRNA/shRNA delivery, biodistribution, pharmacokinetics, and the therapeuticeffect. In this review article, we summarize the current status of in vivo imaging of RNAi. The molecular imaging techniquesthat have been employed include bioluminescence/fluorescence imaging, magnetic resonance imaging/spectroscopy, positron emission tomography, single-photon emission computed tomography, and various combinationsof these techniques. Further development of non-invasive imaging strategies for RNAi, not only focusing on the deliveryof siRNA/shRNA but also the therapeutic efficacy, is critical for future clinical translation. Rigorous validation willbe needed to confirm that biodistribution of the carrier is correlated with that of siRNA/shRNA, since imaging only detectsthe label (e.g. radioisotopes) but not the gene or carrier themselves. It is also essential to develop multimodality imagingapproaches for realizing the full potential of therapeutic RNAi, as no single imaging modality may be sufficient tosimultaneously monitor both the gene delivery and silencing effect of RNAi.