Inhibition of Moloney murine leukemia virus integration using polyamides targeting the long-terminal repeat sequences.
The retroviral integrase (IN) carries out the integration of the viral DNA into the host genome. Both IN and the DNA sequences at the viral long-terminal repeat (LTR) are required for the integration function. In this report, a series of minor groove binding hairpin polyamides targeting sequences within terminal inverted repeats of the Moloney murine leukemia virus (M-MuLV) LTR were synthesized, and their effects on integration were analyzed. Using cell-free in vitro integration assays, polyamides targeting the conserved CA dinucleotide with cognate sites closest to the terminal base pairs were effective at blocking 3' processing but not strand transfer. Polyamides which efficiently inhibited 3' processing and strand transfer targeted the LTR sequences through position 9. Polyamides that inhibited integration were effective at nanomolar concentrations and showed subnanomolar affinity for their cognate LTR sites. These studies highlight the role of minor groove interactions within the LTR termini for retroviral integration.
Yang
Fan
F
Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway 08854, USA.
Belitsky
Jason M
JM
Villanueva
Rodrigo A
RA
Dervan
Peter B
PB
Roth
Monica J
MJ
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D004279:DNA, Viral / Q000187:drug effects / Q000235:genetics; D015195:Drug Design; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008979:Moloney murine leukemia virus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D009757:Nylons / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020079:Terminal Repeat Sequences / Q000187:drug effects*; D016662:Virus Integration / Q000187:drug effects* / Q000235:genetics*
D004279:DNA, Viral; D009757:Nylons