Published online 5 May 2006
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Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
1 UPR 9002 du CNRS conventionnée à l'Université Louis Pasteur, IBMC 15 rue René Descartes, 67084, Strasbourg cedex, France 2 UMR 7123 CNRS—Université Louis Pasteur, Institut Le Bel 4 rue Blaise Pascal, BP 1032/F, 67070, Strasbourg cedex, France 3 UMR 544 INSERM—Université Louis Pasteur, Institut de Virologie 3 rue Koberlé, 67000 Strasbourg, France
*To whom correspondence should be addressed. Tel: +33388417002; Fax: +33388602218; Email: P.Dumas{at}ibmc.u-strasbg.fr
*Correspondence may also be addressed to Roland Marquet. Tel: +33388417054; Fax: +33388602218; Email: R.Marquet{at}ibmc.u-strasbg.fr
Received March 15, 2006. Accepted April 12, 2006.
The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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