Eilatin Ru(II) Complexes Display Anti-HIV Activity and Enantiomeric Diversity in the Binding of RNA

• Published in: Chembiochem : a European journal of chemical biology 2002-08, Vol.3 (8), p.766-771
• Main Authors: Luedtke, Nathan W., Hwang, Judy S., Glazer, Edith C., Gut, Dalia, Kol, Moshe, Tor, Yitzhak
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Binding, Competitive; DNA - metabolism; DNA recognition; Dose-Response Relationship, Drug; Ethidium - chemistry; Ethidium - metabolism; Genes, env - drug effects; Genes, env - physiology; HeLa Cells; HIV; HIV-1 - drug effects; Humans; medicinal chemistry; Molecular Sequence Data; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Phenanthrolines - chemistry; Phenanthrolines - metabolism; Phenanthrolines - pharmacology; Protein Binding; RNA - metabolism; RNA recognition; ruthenium; Ruthenium - chemistry; Ruthenium - metabolism; Ruthenium - pharmacology; Stereoisomerism; Transcriptional Activation - drug effects; Transcriptional Activation - physiology
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/1439-7633(20020802)3:8<766::AID-CBIC766>3.0.CO;2-X

Eilatin‐containing octahedral ruthenium complexes inhibit HIV‐1 replication in CD4+ HeLa cells and in human peripheral blood monocytes with IC50 values of approximately 1 μM. Similar metal complexes that lack eilatin display 15–100‐fold lower anti‐HIV activities. [Ru(bpy)2“pre‐eilatin”]2+, a complex that contains a nonplanar analogue of eilatin, shows significantly lower nucleic acid binding and lower anti‐HIV activity than eilatin complexes. This result indicates that the extended planar surface presented by eilatin is important for both activities. Rev peptide and ethidium bromide displacement assays are used to probe the nucleic acid affinity and specificity of Λ‐ and Δ‐[Ru(bpy)2eilatin]2+. Two HIV‐1 RNA sites are compared and a significant binding preference for the Rev response element over the transactivation response region is found. Simple DNA duplexes show a consistent selectivity for Λ‐[Ru(bpy)2eilatin]2+ compared to Δ‐[Ru(bpy)2eilatin]2+, while RNAs show more diverse enantiomeric selectivities. The plane facts: A single carbon–carbon bond (wavy line; see scheme) is essential for the anti‐HIV activity and nucleic acid affinity of octahedral metal complexes that contain eilatin. Fluorescence displacement assays and thermal denaturation techniques revealed the importance of the planarity of eilatin within the context of ruthenium bipyridine complexes. These complexes also showed variable chiral discrimination between simple duplex RNAs.