Abstract
Human immunodeficiency virus (HIV) genomic RNA is packaged into virions as a dimer. The first step of dimerization is the formation of a kissing-loop complex at the so-called dimerization initiation site (DIS). We found an unexpected and fortuitous resemblance between the HIV-1 DIS kissing-loop complex and the eubacterial 16 S ribosomal aminoacyl-tRNA site (A site), which is the target of aminoglycoside antibiotics. Similarities exist not only at the primary and secondary structure level but also at the tertiary structure level, as revealed by comparison of the respective DIS and A site crystal structures. Gel shift, inhibition of lead-induced cleavage, and footprinting experiments showed that paromomycin and neomycin specifically bind to the kissing-loop complex formed by the DIS, with an affinity and a geometry similar to that observed for the A site. Modeling of the aminoglycoside-DIS complex allowed us to identify antibiotic modifications likely to increase the affinity and/or the specificity for the DIS. This could be a starting point for designing antiviral drugs against HIV-1 RNA dimerization.
Highlights
The fight against HIV1 relies essentially on multitherapies targeting two viral enzymes: reverse transcriptase and protease
We found an unexpected and fortuitous resemblance between the Human immunodeficiency virus (HIV)-1 dimerization initiation site (DIS) kissing-loop complex and the eubacterial 16 S ribosomal aminoacyl-tRNA site (A site), which is the target of aminoglycoside antibiotics
Sequence and Structure Similarities between the DIS and the Ribosomal A Site—Sequence specificity of aminoglycoside antibiotics binding to the prokaryotic ribosomal A site has been extensively studied by mutagenesis and footprinting analysis [23,24,25] and by surface plasmon resonance [26]
Summary
The fight against HIV1 relies essentially on multitherapies targeting two viral enzymes: reverse transcriptase and protease. Inhibition of lead-induced cleavage, and footprinting experiments showed that paromomycin and neomycin bind to the kissing-loop complex formed by the DIS, with an affinity and a geometry similar to that observed for the A site. We modeled a DIS kissing-loop complex binding two paromomycin molecules.
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