Critical role of reverse transcriptase in the inhibitory mechanism of CNI-H0294 on HIV-1 nuclear translocation.
HIV-1 replication requires the translocation of viral genome into the nucleus of a target cell. We recently reported the synthesis of an arylene bis(methyl ketone) compound (CNI-H0294) that inhibits nuclear targeting of the HIV-1 genome and thus HIV-1 replication in monocyte cultures. Here we demonstrate that CNI-H0294 inhibits nuclear targeting of HIV-1-derived preintegration complexes by inactivating the nuclear localization sequence of the HIV-1 matrix antigen in a reaction that absolutely requires reverse transcriptase. This drug/reverse transcriptase interaction defines the specificity of its antiviral effect and is most likely mediated by the pyrimidine side-chain of CNI-H0294. After binding to reverse transcriptase, the carbonyl groups of CNI-H0294 react with the nuclear localization sequence of matrix antigen and prevent its binding to karyopherin alpha, the cellular receptor for nuclear localization sequences that carries proteins into the nucleus. Our results provide a basis for the development of a novel class of compounds that inhibit nuclear translocation and that can, in principle, be modified to target specific infectious agents.
Popov
S
S
Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Dubrovsky
L
L
Lee
M A
MA
Pennathur
S
S
Haffar
O
O
aL-Abed
Y
Y
Tonge
P
P
Ulrich
P
P
Rexach
M
M
Blobel
G
G
Cerami
A
A
Bukrinsky
M
M
D000998:Antiviral Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000821:virology*; D002478:Cells, Cultured; D016679:Genome, Viral; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D009000:Monocytes; D009687:Nuclear Proteins / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000502:physiology; D016662:Virus Integration; D014779:Virus Replication / Q000187:drug effects*; D028901:alpha Karyopherins
D000998:Antiviral Agents; C097286:H 0294; D009687:Nuclear Proteins; D011743:Pyrimidines; D014764:Viral Proteins; D028901:alpha Karyopherins; D054303:HIV Reverse Transcriptase