Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus.
Resistance of the reverse transcriptase (RT) of hepatitis B virus (HBV) to the tenofovir nucleotide drug has not been observed since its introduction for treatment of hepatitis B virus (HBV) infection in 2008. In contrast, frequent viral breakthrough and resistance has been documented for adefovir....
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4152281?pdf=render |
| _version_ | 1818988315136753664 |
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| author | Formijn J van Hemert Ben Berkhout Hans L Zaaijer |
| author_facet | Formijn J van Hemert Ben Berkhout Hans L Zaaijer |
| author_sort | Formijn J van Hemert |
| collection | DOAJ |
| description | Resistance of the reverse transcriptase (RT) of hepatitis B virus (HBV) to the tenofovir nucleotide drug has not been observed since its introduction for treatment of hepatitis B virus (HBV) infection in 2008. In contrast, frequent viral breakthrough and resistance has been documented for adefovir. Our computational study addresses an inventory of the structural differences between these two nucleotide analogues and their binding sites and affinities to wildtype (wt) and mutant RT enzyme structures based on in silico modeling, in comparison with the natural nucleotide substrates.Tenofovir and adefovir only differ by an extra CH3-moiety in tenofovir, introducing a center of chirality at the carbon atom linking the purine group with the phosphates. (R)-Tenofovir (and not (S)-tenofovir) binds significantly better to HBV-RT than adefovir. "Single hit" mutations in HBV-RT associated with adefovir resistance may affect the affinity for tenofovir, but to a level that is insufficient for tenofovir resistance. The RT-Surface protein gene overlap in the HBV genome provides an additional genetic constraint that limits the mutational freedom required to generate drug-resistance. Different pockets near the nucleotide binding motif (YMDD) in HBV-RT can bind nucleotides and nucleotide analogues with different affinities and specificities.The difference in binding affinity of tenofovir (more than two orders of magnitude in terms of local concentration), a 30x higher dosage of the (R)-tenofovir enantiomer as compared to conformational isomeric or rotameric adefovir, and the constrained mutational space due to gene overlap in HBV may explain the absence of resistance mutations after 6 years of tenofovir monotherapy. In addition, the computational methodology applied here may guide the development of antiviral drugs with better resistance profiles. |
| first_indexed | 2024-12-20T19:20:37Z |
| format | Article |
| id | doaj.art-97375b3b3bcd470b8e0e1d0a77bc332d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T19:20:37Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-97375b3b3bcd470b8e0e1d0a77bc332d2022-12-21T19:29:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0199e10632410.1371/journal.pone.0106324Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus.Formijn J van HemertBen BerkhoutHans L ZaaijerResistance of the reverse transcriptase (RT) of hepatitis B virus (HBV) to the tenofovir nucleotide drug has not been observed since its introduction for treatment of hepatitis B virus (HBV) infection in 2008. In contrast, frequent viral breakthrough and resistance has been documented for adefovir. Our computational study addresses an inventory of the structural differences between these two nucleotide analogues and their binding sites and affinities to wildtype (wt) and mutant RT enzyme structures based on in silico modeling, in comparison with the natural nucleotide substrates.Tenofovir and adefovir only differ by an extra CH3-moiety in tenofovir, introducing a center of chirality at the carbon atom linking the purine group with the phosphates. (R)-Tenofovir (and not (S)-tenofovir) binds significantly better to HBV-RT than adefovir. "Single hit" mutations in HBV-RT associated with adefovir resistance may affect the affinity for tenofovir, but to a level that is insufficient for tenofovir resistance. The RT-Surface protein gene overlap in the HBV genome provides an additional genetic constraint that limits the mutational freedom required to generate drug-resistance. Different pockets near the nucleotide binding motif (YMDD) in HBV-RT can bind nucleotides and nucleotide analogues with different affinities and specificities.The difference in binding affinity of tenofovir (more than two orders of magnitude in terms of local concentration), a 30x higher dosage of the (R)-tenofovir enantiomer as compared to conformational isomeric or rotameric adefovir, and the constrained mutational space due to gene overlap in HBV may explain the absence of resistance mutations after 6 years of tenofovir monotherapy. In addition, the computational methodology applied here may guide the development of antiviral drugs with better resistance profiles.http://europepmc.org/articles/PMC4152281?pdf=render |
| spellingShingle | Formijn J van Hemert Ben Berkhout Hans L Zaaijer Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus. PLoS ONE |
| title | Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus. |
| title_full | Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus. |
| title_fullStr | Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus. |
| title_full_unstemmed | Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus. |
| title_short | Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus. |
| title_sort | differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis b virus |
| url | http://europepmc.org/articles/PMC4152281?pdf=render |
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