In 2009, the Zimmerman group discovered a compound to target the trinucleotide repeat expanded RNA and DNA that cause DM1. Through rational design, they utilized a triaminotriazine recognition unit to target TT or UU mismatches through a Janus Wedge type binding mode, creating a base triplet with the mismatch. The combined use of an acridine intercalator to pi-pi stack on the target gave a nanomolar binding affinity for TT or UU mismatches over others. Along with high binding affinity, this molecule was shown to displace MBNL from the complex with r(CUG) with a micromolar K Additionally, HIV-1 RNA has been targeted extensively in vitro by RNA-binding small molecules. In 2007, Miller and coworkers used dynamic combinatorial chemistry to screen a compound library against HIV-1 frameshift regulatory stem-loop RNA. They identified a hit compound that was selective for the regulatory sequence with micromolar binding affinity.
In 2011, Butcher and colleagues discovered a frameshifting stimulator (DB213) which bound to HIV-1 FS RNA with moderate binding affinity. An NMR structure of the RNA in complex with DB213, showed that the small molecule bound to the major groove of the RNA duplex. [https://scholar.google.com/citations?hl=en&user=ViAlX_kAAAAJ Schneekloth] and Hargrove have taken a different approach by targeting the HIV-1 TAR RNA hairpin. In a small molecule microarray screening, the Schneekloth group identified a thienopyridine derivative that interacts with HIV-1 TAR RNA hairpin. Further SAR studies provided more information on the structure and binding mode. The lead analogue was found to bind to the 5’-UTR of HIV with an IC of 40 μM for displacing a Tat-derived peptide. The Hargrove group developed a small library of amiloride derivatives with changes at the C(5) and C(6) positions to improve the binding affinity of amiloride to the loop and bulge of the HIV-1 TAR RNA. Using in vitro studies and modeling, they found a hit compound whose inhibition activity was increased by more than 100x compared to the parent amiloride. This compound is reported to be one of the tightest non-aminoglycoside TAR ligands reported to date.