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.