Modeling of the interaction between new ethidium derivatives and TAR RNA of HIV-1

During the HIV-1 replication process, interactions between the first sequen ce of RNA synthesized named TAR RNA and a viral protein named Tat permit a fast and efficient transcription of viral DNA in RNA. Based on the NMR stru cture of TAR RNA found on the PDB, new derivatives of ethidium were designe d by molecular modeling to inhibit this interaction. The studied molecules are composed of three domains: an arginine, a linker, and an ethidium. Thre e linkers of different lengths were considered in the first step, with the TAR RNA-arginine interaction and the intercalation of the ethidium simulate d by docking methods. In a second step, the structure of the TAR RNA was co mpleted to obtain a whole ethidium interaction site and docking of the whol e studied molecules was investigated. Molecules were synthesized and tested on infected cells. The predicted models and activity are in good agreement with the reported experimental results.