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 int o host cells genome, we have investigated the effect of the external D NA binder netropsin on the in vitro insertion of long terminal repeat (LTR) ends of Moloney murine leukemia virus (M.MuLV) as catalysed by i ntegrase purified from baculovirus strain expression vector. In agreem ent 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 bindin g 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 t o A + T rich region of M.MuLV LTR end and inhibition of insertion is s trongly suggested from the inability of the drug to inhibit the insert ion of HIV U3 LTR end which displays a G + C rich sequence. Selective inhibition of integration of viral DNA appears to be feasible using dr ugs recognizing LTR end sequences.