An interlocked dimeric parallel-stranded DNA quadruplex: A potent inhibitor of HIV-1 integrase Journal Article
| Authors: | Phan, A. T.; Kuryavyi, V.; Ma, J. B. ; Faure, A.; Andréola, M. L.; Patel, D. J. |
| Article Title: | An interlocked dimeric parallel-stranded DNA quadruplex: A potent inhibitor of HIV-1 integrase |
| Abstract: | We report on the NMR-based solution structure of the 93del d(GGGGTGGGAGGAGGGT) aptamer, a potent nanomolar inhibitor of HIV-1 integrase. This guanine-rich DNA sequence adopts an unusually stable dimeric quadruplex architecture in K+ solution. Within each 16-nt monomer subunit, which contains one A-(G-G-G-G) pentad sandwiched between two G-G-G-G tetrads, all G-stretches are parallel, and all guanines are anti with the exception of G1, which is syn. Dimer formation is achieved through mutual pairing of G1 of one monomer, with G2, G6, and G13 of the other monomer, to complete G-G-G-G tetrad formation. There are three single-nucleotide double-chain-reversal loops within each monomer fold, such that the first (T5) and third (A12) loops bridge three G-tetrad layers, whereas the second (A9) loop bridges two G-tetrad layers and participates in A-(G-G-G-G) pentad formation. Results of NMR and of integrase inhibition assays on loop-modified sequences allowed us to propose a strategy toward the potential design of improved HIV-1 integrase inhibitors. Finally, we propose a model, based on molecular docking approaches, for positioning the 93del dimeric DNA quadruplex within a basic channel/canyon formed between subunits of a dimer of dimers of HIV-1 integrase. |
| Keywords: | unclassified drug; nonhuman; binding affinity; enzyme inhibition; drug potency; drug design; dna; rna viruses; magnetic resonance spectroscopy; base sequence; dna sequence; dna structure; dimerization; binding sites; human immunodeficiency virus; nucleic acid conformation; structure analysis; anti-hiv agents; nuclear magnetic resonance; monomer; human immunodeficiency virus 1; guanine derivative; potassium; aptamer; potassium ion; dna strand; virus enzyme; virus dna cell dna interaction; integrase inhibitor; dna aptamer; dimeric quadruplex; 93del dimeric dna quadruplex protein; hiv 1 integrase; oligonucleotide t30177; oligonucleotide t30695; oligonucleotide t30923; hiv integrase; integrase inhibitors; hiv 1 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 102 |
| Issue: | 3 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2005-01-18 |
| Start Page: | 634 |
| End Page: | 639 |
| Language: | English |
| DOI: | 10.1073/pnas.0406278102 |
| PUBMED: | 15637158 |
| PROVIDER: | scopus |
| PMCID: | PMC545538 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 93" - "Export Date: 24 October 2012" - "CODEN: PNASA" - "Source: Scopus" |
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