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      HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate

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          Abstract

          HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes: (i) nucleoside analog RT inhibitors (NRTIs), which compete with natural nucleoside substrates and act as terminators of proviral DNA synthesis, and (ii) non-nucleoside RT inhibitors (NNRTIs), which bind to a hydrophobic pocket close to the RT active site. In spite of the efficiency of NRTIs and NNRTIs, the rapid emergence of multidrug-resistant mutations requires the development of new RT inhibitors with an alternative mechanism of action. Recently, several studies reported the discovery of novel non-nucleoside inhibitors with a distinct mechanism of action. Unlike classical NNRTIs, they compete with the nucleotide substrate, thus forming a new class of RT inhibitors: nucleotide-competing RT inhibitors (NcRTIs). In this review, we discuss current progress in the understanding of the peculiar behavior of these compounds.

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          Most cited references69

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          Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor.

          A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer. The polymerase (pol) domain of the 66-kilodalton subunit has a large cleft analogous to that of the Klenow fragment of Escherichia coli DNA polymerase I. However, the 51-kilodalton subunit of identical sequence has no such cleft because the four subdomains of the pol domain occupy completely different relative positions. Two of the four pol subdomains appear to be structurally related to subdomains of the Klenow fragment, including one containing the catalytic site. The subdomain that appears likely to bind the template strand at the pol active site has a different structure in the two polymerases. Duplex A-form RNA-DNA hybrid can be model-built into the cleft that runs between the ribonuclease H and pol active sites. Nevirapine is almost completely buried in a pocket near but not overlapping with the pol active site. Residues whose mutation results in drug resistance have been approximately located.
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            Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance.

            A combinatorial disulfide cross-linking strategy was used to prepare a stalled complex of human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase with a DNA template:primer and a deoxynucleoside triphosphate (dNTP), and the crystal structure of the complex was determined at a resolution of 3.2 angstroms. The presence of a dideoxynucleotide at the 3'-primer terminus allows capture of a state in which the substrates are poised for attack on the dNTP. Conformational changes that accompany formation of the catalytic complex produce distinct clusters of the residues that are altered in viruses resistant to nucleoside analog drugs. The positioning of these residues in the neighborhood of the dNTP helps to resolve some long-standing puzzles about the molecular basis of resistance. The resistance mutations are likely to influence binding or reactivity of the inhibitors, relative to normal dNTPs, and the clustering of the mutations correlates with the chemical structure of the drug.
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              Identification of four conserved motifs among the RNA-dependent polymerase encoding elements.

              Four consensus sequences are conserved with the same linear arrangement in RNA-dependent DNA polymerases encoded by retroid elements and in RNA-dependent RNA polymerases encoded by plus-, minus- and double-strand RNA viruses. One of these motifs corresponds to the YGDD span previously described by Kamer and Argos (1984). These consensus sequences altogether lead to 4 strictly and 18 conservatively maintained amino acids embedded in a large domain of 120 to 210 amino acids. As judged from secondary structure predictions, each of the 4 motifs, which may cooperate to form a well-ordered domain, places one invariant amino acid in or proximal to turn structures that may be crucial for their correct positioning in a catalytic process. We suggest that this domain may constitute a prerequisite 'polymerase module' implicated in template seating and polymerase activity. At the evolutionary level, the sequence similarities, gap distribution and distances between each motif strongly suggest that the ancestral polymerase module was encoded by an individual genetic element which was most closely related to the plus-strand RNA viruses and the non-viral retroposons. This polymerase module gene may have subsequently propagated in the viral kingdom by distinct gene set recombination events leading to the wide viral variety observed today.
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                Author and article information

                Journal
                Viruses
                Viruses
                Molecular Diversity Preservation International (MDPI)
                1999-4915
                April 2010
                30 March 2010
                : 2
                : 4
                : 880-899
                Affiliations
                [1 ] Istituto di Genetica Molecolare, IGM-CNR, Via Abiategrasso 207, 27100 Pavia, Italy; E-Mail: maga@ 123456igm.cnr.it (G.M.)
                [2 ] Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy; E-Mails: marcoradi@ 123456gmail.com (M.R.); botta.maurizio@ 123456gmail.com (M.B.)
                [3 ] Architecture et Réactivité des ARN, Université de Strasbourg, CNRS, 15 rue René Descartes, F-67084 Strasbourg, France; E-Mail: ma.gerard@ 123456ibmc.u-strasbg.fr (M.-A.G.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: e.ennifar@ 123456ibmc-cnrs.unistra.fr ; Tel.: +33-388-417-002; Fax: +33-388-602-218.
                Article
                viruses-02-00880
                10.3390/v2040880
                3185657
                21994659
                74198882-a63c-4101-98b6-519fe0ee6894
                © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 22 January 2010
                : 20 February 2010
                : 5 March 2010
                Categories
                Review

                Microbiology & Virology
                competitive inhibitors,reverse transcriptase,hiv
                Microbiology & Virology
                competitive inhibitors, reverse transcriptase, hiv

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