reverse transcriptase
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Článek shrnuje základní poznatky o farmakokinetickém profilu, metabolizmu a lékových interakcích rilpivirinu, nejnovějšího perorálního nenukleosidového inhibitoru reverzní transkriptázy 2. generace, který je určen pro dosud neléčené pacienty s HIV-1 infekcí. Faktor, který dominantně určuje vysokou rezistenční bariéru RPV, je jeho konformační flexibilita a adaptabilita, což je unikátní vlastnost diarylpyrimidinových inhibitorů (DAPY inhibitory - NNRTI 2. generace). Jsou analyzovány multicentrické studie ECHO a THRIVE, které prokázaly non-inferioritu RPV k EFV, jeho příznivý bezpečnostní profil a signifikantně méně nežádoucích účinků. Závěrem jsou zmíněna aktuální terapeutická doporučení pro léčbu onemocnění HIV/AIDS a místo rilpivirinu v současných terapeutických režimech.
The article summarizes the basic facts about the pharmacokinetic profile, metabolism and drug interactions of rilpivirine (RPV). This is the latest orally administered second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for antiretroviral-naive patients with HIV-l infection. Conformational flexibility and adaptabihty are the factors that dominantly determine the high resistance barrier of RPV and are the unique features of diarylpyrimidine inhibitors (DAPY inhibitors - 2nd-generation NNRTIs). Multicentre Studies ECHO and THRIVE are also reviewed. Current guidelines for the treatment of HIV/AIDS are mentioned as well as the role of RPV in current therapeutic regimens.
- MeSH
- HIV infekce farmakoterapie imunologie metabolismus MeSH
- inhibitory reverzní transkriptasy * farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- lékové interakce MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- nitrily * farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- pyrimidiny * farmakokinetika metabolismus terapeutické užití MeSH
- Check Tag
- lidé MeSH
In this study, 27 HIV-1-positive patients on long-term highly active antiretroviral therapy (HAART) in the Czech Republic were followed for a period of up to 7 years. Variability of the HIV-1 protease (PR) sequence common in the Czech Republic was observed. Under the pressure of inhibitors of protease (PRIs) and reverse transcriptase (RTIs) mutations in PR were detected. Development of resistance to PRIs was followed by a decrease in CD4 count and increase in viral load. The dynamics of viral load closely corresponded to the accumulation of specific primary mutations in PR and RT. Out of 27 patients 18 developed resistance to PRIs and the prolonged therapy led to the accumulation of a higher number of amino acid changes associated with the resistance and, consequently, cross-resistance to several PRIs was observed. These multi-resistant variants of HIV-1 with mutations in PR could not be inhibited sufficiently with PRIs that are currently available in clinical practice. Efficient yet temporary suppression of viral replication was achieved by a lopinavir (LPV) treatment.
- MeSH
- financování organizované MeSH
- genotyp MeSH
- HIV infekce farmakoterapie virologie MeSH
- HIV reverzní transkriptasa genetika MeSH
- HIV-1 genetika izolace a purifikace účinky léků MeSH
- HIV-proteasa genetika MeSH
- inhibitory HIV-proteasy aplikace a dávkování terapeutické užití MeSH
- látky proti HIV aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- počet CD4 lymfocytů MeSH
- progrese nemoci MeSH
- substituce aminokyselin MeSH
- virová léková rezistence genetika MeSH
- vysoce aktivní antiretrovirová terapie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Geografické názvy
- Česká republika MeSH
Replication of human immunodeficiency virus 1 (HIV-1) involves conversion of its single-stranded RNA genome to double-stranded DNA, which is integrated into the genome of the host. This conversion is catalyzed by reverse transcriptase (RT), which possesses DNA polymerase and RNase H domains. The available crystal structures suggest that at any given time the RNA/DNA substrate interacts with only one active site of the two domains of HIV-1 RT. Unknown is whether a simultaneous interaction of the substrate with polymerase and RNase H active sites is possible. Therefore, the mechanism of the coordination of the two activities is not fully understood. We performed molecular dynamics simulations to obtain a conformation of the complex in which the unwound RNA/DNA substrate simultaneously interacts with the polymerase and RNase H active sites. When the RNA/DNA hybrid was immobilized at the polymerase active site, RNase H cleavage occurred, experimentally verifying that the substrate can simultaneously interact with both active sites. These findings demonstrate the existence of a transient conformation of the HIV-1 RT substrate complex, which is important for modulating and coordinating the enzymatic activities of HIV-1 RT.
HIV-1 reverse transcriptase (RT) possesses both DNA polymerase activity and RNase H activity that act in concert to convert single-stranded RNA of the viral genome to double-stranded DNA that is then integrated into the DNA of the infected cell. Reverse transcriptase-catalyzed reverse transcription critically relies on the proper generation of a polypurine tract (PPT) primer. However, the mechanism of PPT primer generation and the features of the PPT sequence that are critical for its recognition by HIV-1 RT remain unclear. Here, we used a chemical cross-linking method together with molecular dynamics simulations and single-molecule assays to study the mechanism of PPT primer generation. We found that the PPT was specifically and properly recognized within covalently tethered HIV-1 RT-nucleic acid complexes. These findings indicated that recognition of the PPT occurs within a stable catalytic complex after its formation. We found that this unique recognition is based on two complementary elements that rely on the PPT sequence: RNase H sequence preference and incompatibility of the poly(rA/dT) tract of the PPT with the nucleic acid conformation that is required for RNase H cleavage. The latter results from rigidity of the poly(rA/dT) tract and leads to base-pair slippage of this sequence upon deformation into a catalytically relevant geometry. In summary, our results reveal an unexpected mechanism of PPT primer generation based on specific dynamic properties of the poly(rA/dT) segment and help advance our understanding of the mechanisms in viral RNA reverse transcription.
- MeSH
- DNA primery biosyntéza chemie MeSH
- DNA virů MeSH
- HIV reverzní transkriptasa metabolismus fyziologie MeSH
- HIV-1 genetika MeSH
- konformace nukleové kyseliny MeSH
- krystalografie rentgenová metody MeSH
- nukleové kyseliny MeSH
- poly A MeSH
- poly U MeSH
- polynukleotidy MeSH
- puriny chemie MeSH
- ribonukleasa H metabolismus MeSH
- RNA virová chemie MeSH
- sekvence nukleotidů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- MeSH
- cytologické techniky MeSH
- experimentální leukemie MeSH
- močovina MeSH
- myši MeSH
- Check Tag
- myši MeSH
Heterocyclic compounds execute a very important role in drug design and discovery. This article provides the basic milestones of the research for pyrroloaryl and pyrroloheteroaryl based components targeting HIV viral replication cycle. Anti-HIV activity is elaborated for several classes of pyrrolo-compounds as pyrrolopyridines, pyrrolopyrimidines, pyrrolopyridazines, pyrrolobenzodiazepinones, pyrrolobenzothiazepines, pyrrolobenzoxazepinones, pyrrolophenanthridines, pyrroloquinoxalines, pyrrolotriazines, pyrroloquinolines, pyrrolopyrazinones, pyrrolothiatriazines, arylthiopyrroles and pyrrolopyrazolones targeting two essential HIV enzymes, reverse transcriptase and integrase as well as attachment/fusion of HIV virons to the host CD-4 cell. Such attempts were resulted in a discovery of highly potent anti-HIV agents suitable for clinical trials, for example, BMS-378806, BMS-585248, BMS-626529, BMS-663068, BMS-488043 and BMS-663749, etc. as anti-HIV attachment agents, triciribine, QX432, BI-1 and BI-2 as HIV RT inhibitors which are in preclinical or clinical development. Mechanism of action of compounds presented in this article towards the suppression of HIV attachment/fusion as well as against the activities of HIV enzymes reverse transcriptase and integrase has been discussed. Relationships of new compounds' molecular framework and HIV viral target has been overviewed in order to facilitate further construction of promising anti-HIV agents in future drug discovery process.
- MeSH
- HIV infekce farmakoterapie virologie MeSH
- HIV-integrasa metabolismus MeSH
- HIV účinky léků enzymologie fyziologie MeSH
- inhibitory HIV fúze chemie farmakologie MeSH
- inhibitory HIV-integrasy chemie farmakologie MeSH
- inhibitory reverzní transkriptasy chemie farmakologie MeSH
- látky proti HIV chemie farmakologie MeSH
- lidé MeSH
- objevování léků MeSH
- pyrroly chemie farmakologie MeSH
- replikace viru účinky léků MeSH
- reverzní transkriptasa metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Acta Universitatis upsaliensis. Comprehensive summaries of Uppsala dissertations from the Faculty of Medicine, ISSN 0282-7476 No. 783
63 s. ; 26 cm
