Inhibition of Moloney murine leukemia virus integration using polyamides targeting the long-terminal repeat sequences

TY - JOUR

T1 - Inhibition of Moloney murine leukemia virus integration using polyamides targeting the long-terminal repeat sequences

AU - Yang, Fan

AU - Belitsky, Jason M.

AU - Villanueva, Rodrigo A.

AU - Dervan, Peter B.

AU - Roth, Monica J.

PY - 2003/5/27

Y1 - 2003/5/27

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037845167&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037845167&partnerID=8YFLogxK

U2 - https://doi.org/10.1021/bi034177s

DO - https://doi.org/10.1021/bi034177s

M3 - Article

C2 - 12755629

SN - 0006-2960

VL - 42

SP - 6249

EP - 6258

JO - Biochemistry

JF - Biochemistry

IS - 20

ER -