HIV-1 reverse transcriptase and antiviral drug resistance. Part 2

Das, Kalyan; Arnold, Eddy

doi:10.1016/j.coviro.2013.03.014

Cited by 87 publications

(96 citation statements)

References 83 publications

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“…These inhibitors all block the DNA polymerase activity, not that of RNase H. However, RNase H activity is also required for HIV-1 replication. Considering that the emergence of RT inhibitor-resistant HIV-1 variants is a major issue [2], the development of novel HIV-1 RT inhibitors, such as those that block RNase H activity, is an important subject.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the DNA polymerase and RNase H activities of HIV-1 reverse transcriptase and HIV-1 replication by Brasenia schreberi (Junsai) and Petasites japonicus (Fuki) components

et al. 2015

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Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) possesses two distinct enzymatic activities: those of RNA- and DNA-dependent DNA polymerases and RNase H. In the current HIV-1 therapy, all HIV-1 RT inhibitors inhibit the activity of DNA polymerase, but not that of RNase H. We previously reported that ethanol and water extracts of Brasenia schreberi (Junsai) inhibited the DNA polymerase activity of HIV-1 RT [Hisayoshi et al. (2014) J Biol Macromol 14:59-65]. In this study, we screened 43 edible plants and found that ethanol and water extracts of Brasenia schreberi and water extract of Petasites japonicus strongly inhibit not only the activity of DNA polymerase to incorporate dTTP into poly(rA)-p(dT)15 but also the activity of RNase H to hydrolyze the RNA strand of an RNA/DNA hybrid. In addition, these three extracts inhibit HIV-1 replication in human cells, with EC50 values of 1-2 µg/ml. These results suggest that Brasenia schreberi and Petasites japonicus contain substances that block HIV-1 replication by inhibiting the DNA polymerase activity and/or RNase H activity of HIV-1 RT.

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Section: Introductionmentioning

confidence: 99%

Inhibition of the DNA polymerase and RNase H activities of HIV-1 reverse transcriptase and HIV-1 replication by Brasenia schreberi (Junsai) and Petasites japonicus (Fuki) components

et al. 2015

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“…When the polymerase adds a dinucleotide monophosphate (dNMP) to the 3= end of the primer strand, inorganic pyrophosphate (PP i ) is released. Immediately after incorporation of a nucleotide, the 3= end of the primer ϩ1 strand temporarily resides in the N site; translocation moves the end of the primer from the N site to the P site, which allows the cycle to be repeated (1)(2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

“…This type of mutation (collectively referred to as "exclusion mutations") can be either active, if, for example, there is a direct steric clash between the amino acid substitution and the incoming inhibitor, e.g., when the M184V/I mutations cause a steric clash with the oxathiolane ring of 3TC triphosphate (3TCTP), or passive, in which differences in the interactions of the normal dNTPs and the NRTITPs with the mutant RT favor the incorporation of the normal dNTPs over the analog (e.g., Q151M and K65R) (3)(4)(5).…”

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confidence: 99%

“…The AZTMP moiety is removed from the end of the primer by using an ATP-dependent pyrophosphorolysis mechanism that is related to, but distinct from, polymerization reactions run in reverse (2)(3)(4)9). ATP-dependent excision removes the AZTMP from the 3= end, freeing the viral primer strand so that DNA synthesis can continue.…”

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confidence: 99%

“…Structural and modeling studies have shown that the T215Y mutation is one of two (with K70R) primary AZT resistance mutations (2)(3)(4)(5). AZT-resistant HIV-1 RT transfers the AZTMP from the end of the DNA primer to the ␥-phosphate of the ATP, forming a dinucleoside tetraphosphate and producing a free 3=-OH group at the end of the primer strand (Fig.…”

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confidence: 99%

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Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase

Boyer

Das

Arnold

et al. 2015

Antimicrob Agents Chemother

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bAlthough anti-human immunodeficiency virus type 1 (HIV-1) therapies have become more sophisticated and more effective, drug resistance continues to be a major problem. Zidovudine (azidothymidine; AZT) was the first nucleoside reverse transcriptase (RT) inhibitor (NRTI) approved for the treatment of HIV-1 infections and is still being used, particularly in the developing world. This drug targets the conversion of single-stranded RNA to double-stranded DNA by HIV-1 RT. However, resistance to the drug quickly appeared both in viruses replicating in cells in culture and in patients undergoing AZT monotherapy. The primary resistance pathway selects for mutations of T215 that change the threonine to either a tyrosine or a phenylalanine (T215Y/ F); this resistance pathway involves an ATP-dependent excision mechanism. The pseudo-sugar ring of AZT lacks a 3= OH; RT incorporates AZT monophosphate (AZTMP), which blocks the end of the viral DNA primer. AZT-resistant forms of HIV-1 RT use ATP in an excision reaction to unblock the 3= end of the primer strand, allowing its extension by RT. The T215Y AZT resistance mutation is often accompanied by two other mutations, M41L and L210W. In this study, the roles of these mutations, in combination with T215Y, were examined to determine whether they affect polymerization and excision by HIV-1 RT. The M41L mutation appears to help restore the DNA polymerization activity of RT containing the T215Y mutation and also enhances AZTMP excision. The L210W mutation plays a similar role, but it enhances excision by RTs that carry the T215Y mutation when ATP is present at a low concentration. Generally speaking, most mutations in HIV-1 reverse transcriptase (RT) have a negative impact on the enzyme; the primary mutations that cause zidovudine (AZT) resistance are not exceptions. In some cases, secondary mutations are selected in viruses that are replicating in patients because these mutations help to compensate for the deleterious effects of primary resistance mutations. In other cases, the most important effect of a secondary mutation is to cause a further decrease in the susceptibility of the virus to the inhibitor. In this report, we have analyzed the effects of the secondary mutations M41L and L210W, in the presence of the primary mutation T215Y, on both ATP-dependent AZTMP excision and polymerase activities of HIV-1 RT to determine whether these secondary mutations enhance the excision of AZTMP by RT and/or act as compensatory mutations that partially restore the reduced polymerase activity of the T215Y mutant.During the replication of HIV-1, the single-stranded RNA genome is converted into double-stranded DNA by HIV-1 RT. This conversion requires both enzymatic activities of RT: a DNA polymerase that can copy either an RNA or a DNA template and an RNase H that cleaves RNA if, and only if, it is part of an RNA/DNA duplex. Like many DNA polymerases, RT requires both a template and a primer; nucleotides are added sequentially to the 3= end of the primer strand by the polymerase activity of...

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Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

2018

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Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) have always been an important part of the anti‐HIV‐1 combination therapy known as combination antiretroviral therapy (cART) since 1996. The use of NNRTIs for about 22 years has led to some mutations in the residues that compose the reverse transcriptase active site, resulting in the emergence of drug‐resistant viruses. Thus, the search for new potent NNRTIs with an improved safety profile and activity against drug‐resistant HIV strains is indispensable, and many hit and lead NNRTIs have been discovered in the last decade. This review provides an overview of the development in this field from 2013 to August 2018.

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HIV-1 reverse transcriptase and antiviral drug resistance. Part 2

Cited by 87 publications

References 83 publications

Inhibition of the DNA polymerase and RNase H activities of HIV-1 reverse transcriptase and HIV-1 replication by Brasenia schreberi (Junsai) and Petasites japonicus (Fuki) components

Inhibition of the DNA polymerase and RNase H activities of HIV-1 reverse transcriptase and HIV-1 replication by Brasenia schreberi (Junsai) and Petasites japonicus (Fuki) components

Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

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