The process by which DNA is transcribed to messenger RNA (mRNA), which is then translated into protein, is central to our understanding of molecular biology. Although DNA transcription is a well-established target for drug development, in the relatively new field of RNA targeting there have been few advances in our understanding of what happens after transcription, specifically during translation. PTC Therapeutics aims to identify points of intervention in RNA translation as novel drug targets. (Click here for company profile.)

PTC Therapeutics has developed three proprietary technologies to screen for, and identify, small-molecule drug targets within the RNA translation process. First, targeted ribonucleic acid chemistry (TRAC) identifies molecules that bind with high specificity to RNA and modulate RNA function. TRAC is performed under physiological conditions allowing RNAs of interest to retain their native structures, facilitating the identification of molecules that modulate function. PTC also has RNA-Screen Translation and RNA-Screen Turnover platforms that identify, respectively, molecules that modulate different aspects of the translation process, and those that affect specific steps in the turnover and processing of cellular RNA. Molecules identified by the RNA-Screen Turnover platform can promote either substantial increases or decreases in RNA levels. The initial technologies were developed by Peltz and colleagues at the University of Medicine and Dentistry of New Jersey (Piscataway, NJ), during the early 1990s, and were licensed to PTC Therapeutics.

PTC Therapeutics is hoping to develop orally active drugs to treat a variety of diseases including cystic fibrosis and Duchenne muscular dystrophy—both inherited diseases arising from nonsense genetic mutations that lead to the synthesis of an mRNA that contains an inappropriate stop codon. The premature stop codon results in the synthesis of a truncated protein, which may be inactive or insufficient for normal function. In addition, most common cancers result from frameshift and nonsense mutations in regulatory genes (e.g., p53, BRCA1, BRCA2, and APC). Suppressing the effects of these mutations by restoring RNA translation can inhibit blood vessel formation, boost antitumor immune responses, and induce apoptosis in the cancer cells.

RNA targeting is also being tried against HIV, against hepatitis C, and also in the search for new antibacterial and antifungal drugs. For example, PTC Therapeutics is using its TRAC platform to find inhibitors for Tat–TAR, the interaction between a viral protein and RNA structure that is essential for replication of HIV-1 virus.

PTC's main collaborator to date has been Tularik (S. San Francisco, CA). Together the companies have developed high-throughput screens for over 700,000 compounds in both cell-based and in vitro assays, and lead candidates have been identified and characterized in secondary assays. Other companies focusing on RNA and the post-transcription process include the emerging company Message Pharmaceuticals (Malvern, PA), as well as Boulder, Colorado–based Ribozyme Pharmaceuticals and its spinoff, Atugen.