Terpyridyl ruthenium complexes as visible spectral probe for poly(A) RNA and bifunctional TAR RNA binders and HIV-1 reverse transcriptase inhibitors

Terpyridyl Ru(II) complex with low cytotoxicity to normal cells could bind to HIV-1 TAR RNA tightly and selectively by hydrogen bonds and electrostatic attraction, and efficiently inhibit the M-MuLV and HIV-1 reverse transcriptases. • HIV-1 TAR RNA selective binding by terpyridyl Ru(II) complexes. • Terpyridyl Ru(II) complex generating sensitive spectroscopic response to the poly(A) RNA. • Reverse transcriptase inhibition by terpyridyl Ru(II) complexes. • Highly active HIV-1 RT inhibitors with low cytotoxicity to normal cells. HIV-1 reverse transcriptase (RT) inhibitors play essential role in anti-HIV therapy. The vast majority of them target the enzymes, while very few are able to bind to the viral RNA. Here we designed and synthesized two new terpyridyl Ru(II) complexes with HIV-1 TAR RNA binding groups. The complex RuTz2 exhibited a remarkable selectivity for poly(A) RNA over calf thymus DNA, total RNA and yeast transfer RNA, generated significant visible spectral response and inhibited the reverse transcription of poly(A) RNA to poly(dT) cDNA by M-MuLV RT. Moreover, RuTz2 was found to target the HIV-1 TAR RNA tightly and selectively by molecular recognition of hydrogen bonds, further stabilize the Ru(II)-RNA binding complex by electrostatic attraction, and efficiently inhibit the HIV-1 RT. These terpyridyl Ru(II) complexes also showed low toxicity to normal cells, which would greatly reduce its harmful side-effect on normal cells in drug application. This work also provides valuable drug design strategies for AIDS and other RT related diseases researches, such as HCV, EBOV and SARS-CoV-2.