Neamine dimers targeting the HIV-1 TAR RNA.
Natural aminoglycoside antibiotics, such as neomycin, target bacterial ribosomal RNA. Neomycin also binds strongly to HIV TAR and RRE RNA through the predominant interactions of its neamine core. In the search for antiviral agents targeting multiple binding sites for aminoglycosides in RNA, we report here the synthesis of new neamine dimers and a trimer in which the neamine cores are connected by different linking chains attached at the 4'- and/or 5-positions. Inhibition of TAR-Tat complexation by these oligomers was studied via fluorimetric binding assays performed under two ionic strengths. All dimers strongly inhibit TAR-Tat association, with IC50 values 17-85 times better than the value obtained with neomycin. These results demonstrate that modifying neamine at the 4'- or the 5-position is a promising strategy in the search for antiviral agents.
Riguet
Emmanuel
E
Département de Pharmacochimie Moléculaire, UMR 5063 CNRS/Université Joseph Fourier-Grenoble I, ICMG FR 2607, 5 Avenue de Verdun, BP 138 F-38243 Meylan, France.
Désiré
Jérôme
J
Boden
Oliver
O
Ludwig
Verena
V
Göbel
Michael
M
Bailly
Christian
C
Décout
Jean-Luc
JL
D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D019281:Dimerization; D016503:Drug Delivery Systems; D005601:Framycetin / Q000138:chemical synthesis* / Q000494:pharmacology; D015696:Gene Products, tat / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D000998:Antiviral Agents; D015696:Gene Products, tat; D005601:Framycetin; C488396:neamine