HIV-1-Specific Reverse Transcriptase Inhibitors Show Differential Activity against HIV-1 Mutant Strains Containing Different Amino Acid Substitutions in the Reverse Transcriptase

Balzarini, Jan; Karlsson, Anna; Pérez‐Pérez, María‐Jesús; Vrang, Lotta; Walbers, Johan; Zhang, Hong; Öberg, Bo; Vandamme, Anne‐Mieke; Camarasa, Marı́a-José; Clercq, Erik De

doi:10.1006/viro.1993.1027

Cited by 152 publications

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“…It is clear from the interaction energies (Table 3) tacts with Y 181 and Y188 are more important than those with the other aromatic residues. The significance of both Y18 I and Y188 (as well as K103) to the binding of nevirapine has been dramatically shown in mutagenesis experiments (Nunberg et al, 1991;Richman et al, 1991;Larder, 1992;Mellors et al, 1992a and b;Sardana et al, 1992;Schleif et al, 1992;Bacolla et al, 1993;Balzarini et al, 1993;Debyser et al, 1993). The conservative substitutions of Y 181F or Y188F only slightly decreased inhibition by nevirapine, whereas the more radical substitution of isoleucine or cysteine for Y181 or Y 188, respectively, resulted in an enzyme that was resistant to nevirapine.…”

Section: Discussion Of Results From Modeling Each Inhibitor Nevirapinementioning

confidence: 98%

“…Like the nucleoside drugs, however, the nonnucleoside inhibitors have been shown to induce the development of drug-resistant mutants. A number of studies have implicated the amino acid residues at positions 181 and 188, as well as at positions 100, 103, 106,236, and to a lesser extent 98, 101, 108, 179, and 190, as being important in the development of resistance to the drugs (Nunberg et al, 1991;Mellors et al, 1992a and b;Balzarini et al, 1993;Pauwels et al, 1993;Richman, 1993;Tantillo et al, 1994).…”

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Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

Smith¹,

Hughes²,

Boyer³

et al. 1995

Protein Science

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Computer modeling studies have been carried out on three nonnucleoside inhibitors complexed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), using crystal coordinate data from a subset of the protein surrounding the binding pocket region,Results from the minimizations of solvated complexes of 2-cyclopropyl-4-methyl-5,l l-dihydro-5H-dipyrido[3,2-b :2',3'-e][ 1,4]diazepin-6-0ne (nevirapine), a-anilino-2, 6-dibromophenylacetamide (a-APA), and 8-chloro-tetrahydro-imidazo(4,5,l-jk)(l,4)-benzodiazepin-2(IH)-thione (TIBO) show that all three inhibitors maintain a very similar conformational shape, roughly overlay each other in the binding pocket, and appear to function as 7r-electron donors to aromatic side-chain residues surrounding the pocket. However, side-chain residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waals contacts. Consequently, the results from the calculated minimizations reveal that only when the inhibitors are modeled in a site constructed from coordinate data obtained from their particular RT complex can the calculated binding energies be relied upon to predict the correct orientation of the drug in the pocket. In the correct site, these binding energies correlate with EC,, values determined for all three inhibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug is endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically more stable and the drug less stable in their complexes as compared to the reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. interactions of the inhibitors with individual residues correlate with crystallographic and site-specific mutational data. a-Stacking interactions are important in binding and correlate with drug HOMO RHF/6-31G* energies. Modeling results are discussed with respect to the mechanism of complex formation and the design of nonnucleoside inhibitors that will be more effective against mutants of HIV-1 RT that are resistant to the currently available drugs.

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Section: Discussion Of Results From Modeling Each Inhibitor Nevirapinementioning

confidence: 98%

mentioning

confidence: 99%

Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

Smith¹,

Hughes²,

Boyer³

et al. 1995

Protein Science

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“…§1734 solely to indicate this fact. occur in the segments composed of RT amino acids 98-108, 179-190, and 230-236 (9)(10)(11)(12)(13)(14)(15)(16). Especially the Y181-*C RT mutant appears with many chemically distinct compounds, including different NNRTI combinations (12).…”

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confidence: 99%

Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants.

Kleim¹,

Rösner²,

Winkler³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The quinoxaline nonnucleoside RT inhibitor (NNRTI) (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for drug-resistant HIV-1 variants in vitro. The viruses first developed mutations affecting the NNRTIbinding pocket, and five of six strains displayed the RT G190--E substitution, which is characteristic for HIV-1 resistance against quinoxalines. In one variant, a new mutant (G190->Q) most likely evolved from preexisting G190->E mutants. The negative charge introduced by the G190->E substitution was maintained at that site of the pocket by simultaneous selection for V179--D together with G190--Q. After continued exposure to the drug, mutations at positions so far known to be specific for resistance against nucleoside RT inhibitors (NRTIs) (L74-*V/I and V75->L/I) were consistently detected in all cultures. The inhibitory activities of the cellular conversion product of 2',3'-dideoxyinosine (ddl, didanosine), 2',3'-dideoxyadenosine (ddA) and of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine) against these late-passage viruses were shown to be enhanced with the L74->V/I RT mutant virus as compared with the wild-type (wt) HIV-1MN isolate. Clonal analysis proved linkage of the codon 74 and codon 75 mutations to the NNRTI-specific mutations in all RT gene fragments. The nonnucleoside-and nucleoside-resistance mutation sites are separated by approximately 35 A. We propose that the two sites "communicate" through the template-primer which is situated in the DNAbinding cleft between these two sites. Quinoxalines cause high selective pressure on HIV-1 replication in vitro; however, the implication of these findings for the treatment of infection has yet to be determined. Viral resistance against both nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs) of human immunodeficiency virus type 1 (HIV-1) replication develops in vitro (cell culture) and in vivo (patients). NRTIs select for RT amino acid substitutions at positions that can be allocated to different structural elements of the protein in the range of residue numbers 41-219 (1-5). A molecular mechanism for some alterations can be assumed on the basis of the RT crystal structure (6-8). In contrast, NNRTI-specific substitutions map exclusively to those protein secondary structure elements that together form a lipophilic pocket within the palm domain of the p66 RT subunit. All NNRTIs are believed to bind to this region, and mutations selected for by these drugs usuallyThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. occur in the segments composed of RT amino acids 98-108, 179-190, and 230-236 (9-16). Especially the Y181-*C RT mutant appears with many chemically distinct compounds, including different NNRTI combinations (12).6-Chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4-dihydroqu...

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“…The assay procedure was essentially as described (35). 0.05% Triton X-100, 10 til of inhibitor solution (containing various concentrations ofthe test compounds), and 5 ,ul ofthe HIV-1(IIIB) and HIV-1/TSAO-m3T RT preparations.…”

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confidence: 99%

Human immunodeficiency virus type 1 (HIV-1) strains selected for resistance against the HIV-1-specific [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro- 5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)]-beta-D-pentofurano syl (TSAO) nucleoside analogues retain sensitivity to HIV-1-specific nonnucleoside inhibitors.

Balzarini

Karlsson

Vandamme

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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We recently reported that a newly discovered class of nucleoside analogues--[2',5'-bis-O-(tert-butyldimethylsilyl)- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)]-beta-D - pentofuranosyl derivatives of pyrimidines and purines (designated TSAO)--are highly specific inhibitors of human immunodeficiency virus type 1 (HIV-1) and targeted at the nonsubstrate binding site of HIV-1 reverse transcriptase (RT). We now find that HIV-1 strains selected for resistance against three different TSAO nucleoside derivatives retain sensitivity to the other HIV-1-specific nonnucleoside derivatives (tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine, nevirapine, and pyridinone L697,661, as well as to the nucleoside analogues 3'-azido-3'-deoxythymidine, ddI, ddC, and 9-(2-phosphonylmethoxyethyl)adenine. Pol gene nucleotide sequence analysis of the TSAO-resistant and -sensitive HIV-1 strains revealed a single amino acid substitution at position 138 (Glu-->Lys) in the RT of all TSAO-resistant HIV-1 strains. HIV-1 RT in which the Glu-138-->Lys substitution was introduced by site-directed mutagenesis and expressed in Escherichia coli could not be purified because of rapid degradation. However, HIV-1 RT containing the Glu-138-->Arg substitution was stable. It lost its sensitivity to the TSAO nucleosides but not to the other HIV-1-specific RT inhibitors (i.e., TIBO and pyridinone). Our findings point to a specific interaction of the 4''-amino group on the 3'-spiro-substituted ribose moiety of the TSAO nucleosides with the carboxylic acid group of glutamic acid at position 138 of HIV-1 RT.

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HIV-1-Specific Reverse Transcriptase Inhibitors Show Differential Activity against HIV-1 Mutant Strains Containing Different Amino Acid Substitutions in the Reverse Transcriptase

Cited by 152 publications

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Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants.

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