Multivalent binding oligomers inhibit HIV Tat-TAR interaction critical for viral replication.
We describe the development of a new type of scaffold to target RNA structures. Multivalent binding oligomers (MBOs) are molecules in which multiple sidechains extend from a polyamine backbone such that favorable RNA binding occurs. We have used this strategy to develop MBO-based inhibitors to prevent the association of a protein-RNA complex, Tat-TAR, that is essential for HIV replication. In vitro binding assays combined with model cell-based assays demonstrate that the optimal MBOs inhibit Tat-TAR binding at low micromolar concentrations. Antiviral studies are also consistent with the in vitro and cell-based assays. MBOs provide a framework for the development of future RNA-targeting molecules.
Wang
Deyun
D
Laboratory of Bioorganic Chemistry, NIDDK, NIH, DHHS, Bethesda, MD 20892, USA. appellad@niddk.nih.gov
Iera
Jaclyn
J
Baker
Heather
H
Hogan
Priscilla
P
Ptak
Roger
R
Yang
Lu
L
Hartman
Tracy
T
Buckheit
Robert W
RW
Desjardins
Alexandre
A
Yang
Ao
A
Legault
Pascale
P
Yedavalli
Venkat
V
Jeang
Kuan-Teh
KT
Appella
Daniel H
DH
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019380:Anti-HIV Agents; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus