S. Popov et al., CRITICAL ROLE OF REVERSE-TRANSCRIPTASE IN THE INHIBITORY MECHANISM OFCNI-H0294 ON HIV-1 NUCLEAR TRANSLOCATION, Proceedings of the National Academy of Sciences of the United Statesof America, 93(21), 1996, pp. 11859-11864
HIV-1 replication requires the translocation of viral genome into the
nucleus of a target cell. We recently reported the synthesis of an ary
lene bis(methyl ketone) compound (CNI-H0294) that inhibits nuclear tar
geting of the HIV-1 genome and thus HIV-1 replication in monocyte cult
ures. Here we demonstrate that CNI-H0294 inhibits nuclear targeting of
HIV-1-derived preintegration complexes by inactivating the nuclear lo
calization sequence of the HIV-1 matrix antigen in a reaction that abs
olutely requires reverse transcriptase. This drug/reverse transcriptas
e interaction defines the specificity of its antiviral effect and is m
ost likely mediated by the pyrimidine side-chain of CNI-H0294. After b
inding to reverse transcriptase, the carbonyl groups of CNI-H0294 reac
t with the nuclear localization sequence of matrix antigen and prevent
its binding to karyopherin alpha, the cellular receptor for nuclear l
ocalization sequences that carries proteins into the nucleus. Our resu
lts provide a basis for the development of a novel class of compounds
that inhibit nuclear translocation and that can, in principle, be modi
fied to target specific infectious agents.