Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs

Abstract Telomerase is a specialized reverse transcriptase that adds GGTTAG repeats to chromosome ends and is upregulated in most human cancers to enable limitless proliferation. Here, we uncover two distinct mechanisms by which naturally occurring oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation. We conduct a series of direct telomerase extension assays in the presence of modified dNTPs on various telomeric substrates. We provide direct evidence that telomerase can add the nucleotide reverse transcriptase inhibitors ddITP and AZT-TP to the telomeric end, causing chain termination. In contrast, telomerase continues elongation after inserting oxidized 2-OH-dATP or therapeutic 6-thio-dGTP, but insertion disrupts translocation and inhibits further repeat addition. Kinetics reveal that telomerase poorly selects against 6-thio-dGTP, inserting with similar catalytic efficiency as dGTP. Furthermore, telomerase processivity factor POT1-TPP1 fails to restore processive elongation in the presence of inhibitory dNTPs. These findings reveal mechanisms for targeting telomerase with modified dNTPs in cancer therapy.

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Application of a colorimetric chain-termination assay for characterization of reverse transcriptase from 3′-azido-2′,3′-deoxythymidine-resistant HIV isolates

Biotechnology and Applied Biochemistry ◽

10.1042/ba20010031 ◽

2002 ◽

Vol 35 (3) ◽

pp. 155 ◽

Cited By ~ 4

Author(s):

Xing-Wu Shao ◽

Sandra Hjalmarsson ◽

Johan Lennerstrand ◽

Bo Svennerholm ◽

Jonas Blomberg ◽

...

Keyword(s):

Reverse Transcriptase ◽

Chain Termination

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Faculty Opinions recommendation of Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725668276.793532496 ◽

2017 ◽

Author(s):

Eric Daar

Keyword(s):

Reverse Transcriptase ◽

Reverse Transcriptase Inhibitors ◽

Nucleoside Reverse Transcriptase Inhibitors ◽

Dose Ranging ◽

Hiv 1

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An Overview of Antiretroviral Agents for Treating HIV Infection in Paediatric Population

Current Medicinal Chemistry ◽

10.2174/0929867325666180904123549 ◽

2020 ◽

Vol 27 (5) ◽

pp. 760-794 ◽

Cited By ~ 3

Author(s):

Rita Melo ◽

Agostinho Lemos ◽

António J. Preto ◽

Beatriz Bueschbell ◽

Pedro Matos-Filipe ◽

...

Keyword(s):

Hiv Infection ◽

Reverse Transcriptase ◽

Targeted Delivery ◽

Highly Active Antiretroviral Therapy ◽

Antiretroviral Drugs ◽

Viral Reservoir ◽

Reverse Transcriptase Inhibitors ◽

Replication Process ◽

Antiretroviral Agents ◽

Multiple Drugs

Paediatric Acquired ImmunoDeficiency Syndrome (AIDS) is a life-threatening and infectious disease in which the Human Immunodeficiency Virus (HIV) is mainly transmitted through Mother-To- Child Transmission (MTCT) during pregnancy, labour and delivery, or breastfeeding. This review provides an overview of the distinct therapeutic alternatives to abolish the systemic viral replication in paediatric HIV-1 infection. Numerous classes of antiretroviral agents have emerged as therapeutic tools for downregulation of different steps in the HIV replication process. These classes encompass Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs), Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs/NtRTIs), INtegrase Inhibitors (INIs), Protease Inhibitors (PIs), and Entry Inhibitors (EIs). Co-administration of certain antiretroviral drugs with Pharmacokinetic Enhancers (PEs) may boost the effectiveness of the primary therapeutic agent. The combination of multiple antiretroviral drug regimens (Highly Active AntiRetroviral Therapy - HAART) is currently the standard therapeutic approach for HIV infection. So far, the use of HAART offers the best opportunity for prolonged and maximal viral suppression, and preservation of the immune system upon HIV infection. Still, the frequent administration of high doses of multiple drugs, their inefficient ability to reach the viral reservoirs in adequate doses, the development of drug resistance, and the lack of patient compliance compromise the complete HIV elimination. The development of nanotechnology-based drug delivery systems may enable targeted delivery of antiretroviral agents to inaccessible viral reservoir sites at therapeutic concentrations. In addition, the application of Computer-Aided Drug Design (CADD) approaches has provided valuable tools for the development of anti-HIV drug candidates with favourable pharmacodynamics and pharmacokinetic properties.

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Cyclopamine, a Naturally Occurring Alkaloid, and Its Analogues May Find Wide Applications in Cancer Therapy

Current Topics in Medicinal Chemistry ◽

10.2174/15680266113139990153 ◽

2013 ◽

Vol 13 (17) ◽

pp. 2208-2215 ◽

Cited By ~ 16

Author(s):

Haikuo Ma ◽

Huan-Qiu Li ◽

Xiaohu Zhang

Keyword(s):

Cancer Therapy ◽

Naturally Occurring

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3D-QSAR Studies of S-DABO Derivatives as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180810112321 ◽

2019 ◽

Vol 16 (8) ◽

pp. 868-881

Author(s):

Yueping Wang ◽

Jie Chang ◽

Jiangyuan Wang ◽

Peng Zhong ◽

Yufang Zhang ◽

...

Keyword(s):

Reverse Transcriptase ◽

Three Dimensional ◽

Predictive Ability ◽

3D Qsar ◽

Binding Mode ◽

Quantitative Structure Activity Relationship ◽

Field Analysis ◽

Reverse Transcriptase Inhibitors ◽

Qsar Studies ◽

Hiv 1

Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1. Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment. Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r2 pred values of 0.843 and 0.723, respectively. Conclusion: The information obtained from the 3D contour maps can be used in designing new SDABO derivatives with improved HIV-1 inhibitory activity.

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