Conformational Changes in HIV-1 Reverse Transcriptase Induced by Nonnucleoside Reverse Transcriptase Inhibitor Binding

Sluis‐Cremer, Nicolas; Temiz, Nuri A.; Bahar, İvet

doi:10.2174/1570162043351093

Cited by 132 publications

(112 citation statements)

References 76 publications

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“…The conformational changes in the NNRTI BP induced by NNRTI binding distort the geometry of the DNA polymerase catalytic site (13), and in addition, NNRTI binding deforms the structural elements that comprise the primer grip which is involved in the positioning of a primer DNA strand into the polymerase active site (19). Either of these changes is able to inhibit the DNA polymerization reaction by preventing establishment of a catalytically competent RT-template/primer-dNTP ternary complex (38). Both NRTIs and NNRTIs are key components of highly active antiretroviral therapy (HAART), which has led to significant declines in HIV-associated morbidity and mortality, but both classes of drugs, like all other antiretrovirals, can be compromised by drug resistance.…”

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confidence: 99%

Molecular Mechanism of Antagonism between the Y181C and E138K Mutations in HIV-1 Reverse Transcriptase

Oliveira

Asahchop

et al. 2012

J Virol

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Etravirine (ETR) is an expanded-spectrum nonnucleoside reverse transcriptase inhibitor (NNRTI) approved for use as an antiretroviral agent in treatment-experienced patients. Y181C and E138K in HIV-1 RT are among 20 different drug resistance mutations associated with ETR. However, E138K can be consistently selected by ETR when wild-type viruses but not viruses containing Y181C are grown in tissue culture. This study was carried out to evaluate any possible mechanisms that might explain antagonism between the Y181C and E138K mutations. Accordingly, we performed tissue culture studies to investigate the evolutionary dynamics of E138K in both a wild-type (WT) and a Y181C background. We also generated recombinant enzymes containing Y181C and E138K alone or in combination in order to study enzyme processivity, rates of processive DNA synthesis, enzyme kinetics, and susceptibility to ETR. We now show that the presence of the Y181C mutation prevented the emergence of E138K in cell culture and that the simultaneous presence of E138K and Y181C impaired each of enzyme activity, processivity, rate of processive DNA synthesis, and deoxynucleoside triphosphate (dNTP) affinity. The addition of E138K to Y181C also decreased the level of resistance to ETR compared to that obtained with Y181C alone.

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confidence: 99%

Molecular Mechanism of Antagonism between the Y181C and E138K Mutations in HIV-1 Reverse Transcriptase

Oliveira

Asahchop

et al. 2012

J Virol

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“…In addition, NNRTIs nevirapine (NVP), efavirenz (EFV), and etravirine (ETR) have also been shown to enhance RT dimerization (55). Biochemical and structural analysis of the inhibition of reverse transcription by NNRTIs reveals that their binding induces conformational changes in RT that distort the precise geometry of the DNA polymerase catalytic site; these conformational changes affect the alignment of the primer terminus and slow down phosphodiester bond formation, as well as restrict domain motions and DNA translocation (48,51,52,54). Some NNRTIs can modulate RNase H activity through long-range interactions and, depending upon the structure of the RNA-DNA hybrid substrate, can lead to the inhibition or stimulation of RNase H activity (21,25,37,45,50).…”

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confidence: 99%

A Novel Molecular Mechanism of Dual Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors

Nikolenko

Delviks-Frankenberry

Pathak

2010

J Virol

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Recently, mutations in the connection subdomain (CN) and RNase H domain of HIV-1 reverse transcriptase (RT) were observed to exhibit dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). To elucidate the mechanism by which CN and RH mutations confer resistance to NNRTIs, we hypothesized that these mutations reduce RNase H cleavage and provide more time for the NNRTI to dissociate from the RT, resulting in the resumption of DNA synthesis and enhanced NNRTI resistance. We observed that the effect of the reduction in RNase H cleavage on NNRTI resistance is dependent upon the affinity of each NNRTI to the RT and further influenced by the presence of NNRTI-binding pocket (BP) mutants. D549N, Q475A, and Y501A mutants, which reduce RNase H cleavage, enhance resistance to nevirapine (NVP) and delavirdine (DLV), but not to efavirenz (EFV) and etravirine (ETR), consistent with their increase in affinity for RT. Combining the D549N mutant with NNRTI BP mutants further increases NNRTI resistance from 3- to 30-fold, supporting the role of NNRTI-RT affinity in our NNRTI resistance model. We also demonstrated that CNs from treatment-experienced patients, previously reported to enhance NRTI resistance, also reduce RNase H cleavage and enhance NNRTI resistance in the context of the patient RT pol domain or a wild-type pol domain. Together, these results confirm key predictions of our NNRTI resistance model and provide support for a unifying mechanism by which CN and RH mutations can exhibit dual NRTI and NNRTI resistance.

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“…This is analogous to the complexity of marine natural products, with a great variety of structures with different degrees of biological activity (De Clercq, 1998). NNRTI have in common the affi nity for the extremely fl exible hydrophobic p66 chain located near the active site (approximately 10 Å away) and located between the β-sheet-6-9-β-β and β-10-12-13-β-β-14 from the palm domain, called the "non-nucleoside inhibitor binding pocket" (NNIBP) (Boyer et al, 1994a(Boyer et al, , 1994bSluis-Cremer et al, 2004;Martin et al, 2010;Zhan et al, 2011). The inhibition mechanism is due to the expansion of the region of NNBIP, since this hydrophobic "pocket" is closed during the active period of TR.…”

Section: Terpenes As Nnrti Models: Looking At Future Anti-hiv Treatmementioning

confidence: 99%

HIV-1 Reverse Transcriptase: a potential target for marine products

Miceli¹,

Souza²,

Rodrigues³

et al. 2012

Rev. bras. farmacogn.

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HIV-1 reverse transcriptase (HIV-1 RT) is a therapeutic target for the treatment of HIV-positive individuals or those already showing AIDS symptoms. In this perspective, the identifi cation of new inhibitors for this enzyme is of great importance in view of the growing viral resistance to the existing treatments. This resistance has compromised the quality of life of those infected with multidrug-resistant strains, whose treatment options are already limited, putting at risk these individuals lives. The literature has recognized marine organisms and their products as natural sources for the identifi cation of new therapeutic options for different pathologies. In this brief review, we consider the structure of HIV-1 RT and its most common inhibitors, as well as some marine diterpenes originally reported as HIV-1 RT inhibitors to encourage the identifi cation and development of new marine antiviral prototypes.

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Conformational Changes in HIV-1 Reverse Transcriptase Induced by Nonnucleoside Reverse Transcriptase Inhibitor Binding

Cited by 132 publications

References 76 publications

Molecular Mechanism of Antagonism between the Y181C and E138K Mutations in HIV-1 Reverse Transcriptase

Molecular Mechanism of Antagonism between the Y181C and E138K Mutations in HIV-1 Reverse Transcriptase

A Novel Molecular Mechanism of Dual Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors

HIV-1 Reverse Transcriptase: a potential target for marine products

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