I met with Dr. Fabris, a senior faculty member here at The RNA Institute to discuss his research program that concentrates on “targets” or potential drug candidates for HIV. Now, in collaboration with Dr. Cara Pager, he is also exploring HCV and Polio. He explained to me how he believes that RNA has enormous potential both as a direct therapeutic and target to be modified via small molecule based drugs. It is the latter, targeted approach with which Dr. Fabris is especially riveted. By aiming for viral RNA already inside of a cell, he told me how “we can use small molecules to circumvent the long-standing problem of the large size and the many negative charges of an RNA drug being delivered, and can potentially find small molecule ligands that “target” and thus interfere with viral genome packaging.”
He continued by discussing how while this traditional interference approach circumvents therapeutic delivery concerns, discovering which ligands could potentially become drug candidates is remarkably challenging.There are vast libraries of molecules to be evaluated which is of course time and labor intensive. In response to this dilemma, Dr. Fabris and his team are creating technologies, analytics and dose sampling techniques that have enabled him to draw data from over 78,000 ligands at a time. Despite this staggering number, Dr. Fabris isn’t trying to create a workhorse-super-core-facility. Rather, he is focusing on innovating solutions that could have a broad impact on early phase RNA drug discovery. From his initial 78,000 he is now investigating 150 ligands that have demonstrated binding potential. Dr. Fabris is hoping to cull the list down to a handful of possible ligands for which he will run biological assays, thus dramatically improving the economic feasibility of early stage drug discovery.
With his graduate student, Jennifer Lippens, Dr. Fabris is also innovating a way to see not only whether binding between a ligand and RNA has occurred, but whether or not the structure of the complex is modified in the process. Since the structure-function relationship is critical to biological understanding and in turn drug discovery, this method could have significant implications.
When talking about his research, Dr. Fabris’ demure demeanor becomes magnetic. Over the loud hum of his mass spectrometers, he lights up and says “You make a hypothesis and the results may be entirely different from what you expected. But because of that, it’s never boring. I’m still very excited each day to do this research.”
Jul 01, 2014