Editorial [Hot topic: RNAi and Related Technologies: Applications in Medicinal Chemistry and Drug Discovery (Guest Editors: Keven Morris and Shelli McAlpine)]

RNA interference (RNAi) is a recently realized technique that allows for the targeted control of gene expression. In some diseases genes are overtly regulated, thus the ability to specifically and potently target the silencing of gene expression has significant medical impact on these disease states. RNAi utilizes small interfering RNAs (siRNAs) or microRNAs (miRNAs) to silence specific genes. There are two modes of RNAi-based regulation in human cells: post-transcriptional gene silencing (PTGS) and transcriptional gene silencing (TGS). There are several nuances in the mechanistic underpinnings in both PTGS and TGS, which are discussed in this issue of “Current Topics in Medicinal Chemistry”. These articles provide a comprehensive review of recent developments in RNAi in human cells and highlight the distinct mechanisms in this state of the art technique. In this issue, articles from 8 research groups actively utilizing RNAi have been compiled to provided a thorough and comprehensive analysis of the current state of RNAi as a therapeutic tool. Dr. Marc S. Weinberg and colleagues opens the issue with an article entitled; “RNA interference therapy or another antisense modality”? In this article RNAi is discussed and mechanistically contrasted with antisense technologies which for several years were the dominant paradigm utilized in regulating gene expression. Indeed it was initial studies by Fire and Mello utilizing antisense RNAs which uncovered the RNAi pathway in C. Elegans. The second review by Dr. Kazsuz Suzuki and colleagues entitled; “Transcriptional targeted RNAs”, discusses the relatively new pathway of small RNA directed transcriptional silencing. This pathway involves small RNAs capable of directing silent state epigenetic changes at gene promoters, and recent investigation suggests that this pathway is endogenous in human cells and relies on long non-coding RNAs for functional gene regulation. Notably, this method of silencing can result in stable epigenetic silencing which can be long-term and passage to daughter cells. Far less is known regarding this molecular pathway but the potential of silencing may be superlative with regards to the well studies RNAi pathway.