Chetomin is a biologically active small molecule that belongs to the class of sporidesmins - epidithiodiketopiperazine fungal metabolites. It has been shown to inhibit the transcription of VEGF, an oncogene primarily responsible for angiogenesis. The mechanism of this downregulation involves allosteric blockage of the CH1 domain of p300/CBP co-activator protein by chetomin. In cells and tissues, the p300/CBP coactivator is involved in a number of other transcriptional processes that are important both in maintenance of health and in establishment of a disease. Our particular interest is in activation of the interferon-induced ADAR gene whose translation product, RNA-dependent adenosine deaminase, is involved in viral life cycle. This activation is initiated by binding of STAT2 homodimer to DNA. We are investigating fundamental questions surrounding the mechanism of STAT2-mediated transcription along with the strategies for its inhibition with designed small molecules derived from chetomin. Our goal is to establish the requirements for specificity and activity of the requisite non-natural transcriptional regulators and their potential for development of transcription-based therapies.