CRITICAL ROLE OF REVERSE-TRANSCRIPTASE IN THE INHIBITORY MECHANISM OFCNI-H0294 ON HIV-1 NUCLEAR TRANSLOCATION

Citation
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
Citations number
30
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
93
Issue
21
Year of publication
1996
Pages
11859 - 11864
Database
ISI
SICI code
0027-8424(1996)93:21<11859:CRORIT>2.0.ZU;2-G
Abstract
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.