The Daily Bulletin Archive

Please join us for the Professional Science Master's seminar "New Strategies for RNA-Targeted HIV Therapeutics," presented by Benjamin L. Miller, Ph.D., from the University of Rochester Medical Center, on Thursday, March 1, from 12:30 to 1:30 p.m. in Science and Mathematics Complex 169.

Abstract
Sequence-selective RNA recognition represents an outstanding unsolved problem for the field of bioorganic chemistry. In contrast to DNA, there are no heuristics that can map an RNA sequence to a synthetic compound that binds only that sequence. Because of the ever-increasing pace of discovery of RNAs with relevance to basic biology and disease, it has become clear that the development of general methods for the design of bioactive RNA-binding compounds is a critical need.

We have developed resin-bound dynamic combinatorial chemistry (RBDCC) as a method for addressing this challenge. RBDCC allows the rapid in situ synthesis and screening of large (>11,000-compound) libraries without the analytical challenges of “traditional” solution-phase dynamic combinatorial libraries. We have applied the RBDCC concept to several RNA targets, including one critical to the life cycle of HIV, and another believed to be responsible for type 1 myotonic dystrophy. This lecture will discuss the development of RBDCC, its use as an enabling tool for identifying sequence-selective RNA binders, and the further development of RBDCC-discovered compounds as lead molecules with target-relevant activity in vitro and in vivo. We will particularly focus on the development of compounds able to alter -1 ribosomal frameshifting (recoding) in HIV, thereby inhibiting viral replication. As protein recoding is a widely used regulatory mechanism in viruses, bacteria, and eukaryotes (including humans), this strategy may have broad utility.