Stavudine Resistance: An Update on Susceptibility following Prolonged Therapy

Lin, Pin‐Fang; Gonzalez, Charles J.; Griffith, Brigitte P.; Friedland, Gerald; Cálvez, Vincent; Ferchal, F; Schinazi, Raymond F.; Shepp, David H.; Ashraf, Amar; Wainberg, Mark A.; Soriano, Vincent; Mellors, John W.; Colonno, Richard J.

doi:10.1177/135965359900400103

Cited by 39 publications

(7 citation statements)

References 40 publications

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“…Consequently, a low selectivity or ability of HIV-1 RT to distinguish between natural dNTP and substrate analogue suggests that it may be more difficult for the virus to develop drug resistance through mutations in RT. Cell culture and clinical data support this suggestion in the case of D4T ( , ).…”

Section: Discussionmentioning

confidence: 67%

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

et al. 2002

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Abacavir (1592U89, or Ziagen) is a powerful and selective inhibitor of HIV-1 viral replication that has been approved by the FDA for treatment of acquired immunodeficiency syndrome. Abacavir is metabolized to the active compound carbovir triphosphate (CBVTP). This compound is a guanosine analogue containing a 2',3'-unsaturation in its planar carbocyclic deoxyribose ring that acts on HIV-1 reverse transcriptase (RT(WT)) as a molecular target, resulting in chain termination of DNA synthesis. A single amino acid change from methionine 184 to valine in HIV-1 RT (RT(M184V)) has been observed clinically in response to abacavir treatment. The ability of the natural substrate, dGTP, or CBVTP to be utilized during DNA- and RNA-directed polymerization by RT(WT) and RT(M184V) was defined by pre-steady-state kinetic parameters. In the case of RT(WT), CBVTP was found to be a surprisingly poor substrate relative to dGTP. In both DNA- and RNA-directed polymerization, a decrease in the efficiency of CBVTP utilization with respect to dGTP was found with RT(M184V), suggesting that this mutation confers resistance at the level of CBVMP incorporation. The relatively low incorporation efficiency for RT(WT) was unanticipated considering earlier studies showing that the triphosphate form of a thymidine nucleoside analogue containing a planar 2',3'-unsaturated ribose ring, D4TTP, was incorporated with high efficiency relative to the natural substrate, dTTP. The difference may be related to the isosteric replacement of oxygen in the deoxyribose ring with carbon. This hypothesis was tested by synthesizing and evaluating D4GTP (the planar 2',3'-unsaturated deoxyribose guanosine analogue that is complementary to D4TTP). In contrast to CBVTP, D4GTP was found to be an excellent substrate for RT(WT) and no resistance was conferred by the M184V mutation, thus providing novel insight into structure-activity relationships for nucleoside-based inhibitors. In this work, we illustrate how an understanding of the molecular mechanism of inhibition and drug resistance led to the discovery of a novel prodrug of D4G. This compound shows promise as a potent antiviral especially with the drug resistant M184V HIV-1 RT that is so often encountered in a clinical setting.

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Section: Discussionmentioning

confidence: 67%

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

et al. 2002

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“…AZT resistant RT mutations can be selected by, and are cross resistant to, D4T (51). To understand the kinetics of D4TMP removal by RT AZTR , similar removal studies were carried out with PP i or ATP and a DNA-DNA primertemplate (Table 4).…”

Section: Equilibrium Binding Constant (K D ) and Maximum Rate Of Remo...mentioning

confidence: 99%

Probing the Molecular Mechanisms of AZT Drug Resistance Mediated by HIV-1 Reverse Transcriptase Using a Transient Kinetic Analysis

et al. 2003

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Several hypotheses have been proposed to explain the development of resistance to the anti-HIV drug AZT. Clinical findings show that AZT resistance mutations in HIV-1 reverse transcriptase (RT) not only reduce susceptibility to thymidine analogues but may also confer multi-dideoxynucleoside resistance. In this report, we describe transient kinetic studies establishing the biochemical effects of AZT resistance mutations in HIV-1 RT on the incorporation and removal of natural and unnatural deoxynucleotides. While the physiological role remains to be elucidated, the largest biochemical difference between wild-type and AZT resistant HIV-1 RT manifested itself during ATP-mediated deoxynucleotide removal. Enhanced removal resulted from an increase in the maximum rate of chain terminator excision, suggesting that mutated residues play a role in the optimal alignment of substrates for ATP-mediated removal. The efficiency of pyrophosphorolysis was not increased by the presence of AZT resistance mutations. However, a 2-fold decrease in the extent of inhibition caused by the next correct nucleotide during pyrophosphorolytic cleavage of a D4TMP chain-terminated primer may illustrate how this mutant can utilize pyrophosphate to enhance resistance. The inability of RT to catalyze removal of a chain terminator from an RNA-RNA primer-template may show how slight changes in selectivity against AZTMP incorporation during the initiation of DNA synthesis can contribute to high-level resistance. Taken together, these results suggest that multiple modes of resistance may be conferred by these mutations. Structure-activity studies of chain terminator removal suggest that analogues that form tight interactions with residues in the RT active site may be more prone to resistance mechanisms mediated by removal.

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“…Regarding d4T, when it is given as the only drug to patients naive to AZT, RT bearing a Val75Thr substitution is selected in 10% of the cases . However, the most important d4T resistance mutations are TAMs . Resistance to ddC, ddI, and 3TC are conferred by single mutations in the pol gene, namely Lys65Arg, , Leu74Val, and Met184Val; − furthermore, cases of multinucleoside and cross resistance exist such as the Gln151Met resistance complex [for a review, see Carvalho et al, Mini.-Rev.…”

Section: Introductionmentioning

confidence: 99%

“…3 However, the most important d4T resistance mutations are TAMs. 4 Resistance to ddC, ddI, and 3TC are conferred by single mutations in the pol gene, namely Lys65Arg, 5,6 Leu74Val, 7 and Met184Val; [8][9][10] furthermore, cases of multinucleoside and cross resistance exist such as the Gln151Met resistance complex [for a review, see Carvalho et 11 There are two main mechanisms by which drug resistance mutations cause reduced viral susceptibility to NRTIs. The first mechanism, discrimination, affects the affinity and or incorporation of the analogue relative to the normal substrate; the second is the excision mechanism.…”

Section: Introductionmentioning

confidence: 99%

Insights on Resistance to Reverse Transcriptase: The Different Patterns of Interaction of the Nucleoside Reverse Transcriptase Inhibitors in the Deoxyribonucleotide Triphosphate Binding Site Relative to the Normal Substrate

2006

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It is presently known that the long-term failure in the treatment of AIDS with the currently available nucleotide reverse transcriptase inhibitors (NRTIs) is related to the development of resistance by reverse transcriptase (RT) at the binding or incorporation level or both, or subsequent to the nucleotide incorporation (excision). To achieve greater insight on the differential interactions of two NRTIs that are mainly discriminated by different mechanisms, 2',3'-didehydro-2',3'-dideoxythymidine-5'-triphosphate (d4TTP, that is, phosphorylated stavudine) and 2',3'-dideoxycytidine-5'-triphosphate (ddCTP, that is, phosphorylated zalcitabine), with the primer/template (p/t) and with the N binding site of reverse transcriptase (RT) in relation to the normal substrate (dNTP), we have conducted a series of molecular dynamics (MD) simulations. We propose that the different resistance profiles arise from the different conformations adopted by the inhibitors at the N site. d4TTP adopts an ideal conformation for catalysis because it forms an ion-dipole intramolecular interaction with the beta-phosphate oxygen of the triphosphate, as does the normal substrate. In ddCTP, the lack of this essential interaction results in a different, noncatalytic conformation.

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Stavudine Resistance: An Update on Susceptibility following Prolonged Therapy

Cited by 39 publications

References 40 publications

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

Probing the Molecular Mechanisms of AZT Drug Resistance Mediated by HIV-1 Reverse Transcriptase Using a Transient Kinetic Analysis

Insights on Resistance to Reverse Transcriptase: The Different Patterns of Interaction of the Nucleoside Reverse Transcriptase Inhibitors in the Deoxyribonucleotide Triphosphate Binding Site Relative to the Normal Substrate

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