Inhibition of the in vitro integration of Moloney murine leukemia virus DNA by the DNA minor groove binder netropsin.
In search of potential inhibitors of integration of retroviral DNA into host cells genome, we have investigated the effect of the external DNA binder netropsin on the in vitro insertion of long terminal repeat (LTR) ends of Moloney murine leukemia virus (M.MuLV) as catalysed by integrase purified from baculovirus strain expression vector. In agreement with the preferential binding of netropsin to A+T rich sequences, footprinting experiments have shown that this drug selectively binds to the 5'-TTTCAT LTR end sequence which is included in the DNA binding site of integrase. This feature results in the potent inhibition of both reactions involved in the insertion process, namely, nucleolytic cleavage and strand transfer. The relation between netropsin binding to A+T rich region of M.MuLV LTR end and inhibition of insertion is strongly suggested from the inability of the drug to inhibit the insertion of HIV U3 LTR end which displays a G+C rich sequence. Selective inhibition of integration of viral DNA appears to be feasible using drugs recognizing LTR end sequences.
Carteau
S
S
Laboratoire de Physicochimie et Pharmacologie des Macromolécules Biologiques, CNRS URA 147, Institut Gustave Roussy, Villejuif, France.
Mouscadet
J F
JF
Goulaouic
H
H
Subra
F
F
Auclair
C
C
D000595:Amino Acid Sequence; D001483:Base Sequence; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D004279:DNA, Viral / Q000378:metabolism*; D066298:In Vitro Techniques; D019426:Integrases; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D009429:Netropsin / Q000737:chemistry / Q000494:pharmacology*; D012091:Repetitive Sequences, Nucleic Acid
D004279:DNA, Viral; D009429:Netropsin; D004254:DNA Nucleotidyltransferases; D019426:Integrases