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Updated: Sep 5, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Awareness of Potential Off-target Effects of Nucleoside Reverse Transcriptase Inhibitors on Telomerase in Patients
Matheus Reck Dutra1, Lucas Reck Dutra1, Juliana Dal-Ri Lindenau1
1Department of Cell Biology, Embryology and Genetics, Biology Science Center, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil.
Introduction/Objective:
Familial Pulmonary Fibrosis (FPF) is a lung disease, a subset of which is associated with mutations in telomere-related genes, causing breathing difficulties and compromising quality of life. Telomere length is maintained and extended by telomerase, a reverse transcriptase enzyme that uses an RNA template, generating repetitive sequences rich in guanosine. However, heterozygous loss-of-function mutations in the TERT gene result in telomerase haploinsufficiency, reducing enzyme activity and contributing to earlier disease onset. In this context, it is important to evaluate the potential effects of NRTIs on telomerase, particularly whether these drugs may inhibit its activity. This review discusses the potential implications of this interaction for patients with FPF.
Methods:
This study is based on a narrative literature search conducted in the PubMed database, using combinations of the relevant keywords, regardless of their year of publication.
Results:
A literature review identified studies investigating the effects of NRTIs on telomerase activity. Overall, the available evidence indicates that several NRTIs, depending on the study design and the specific molecule evaluated, may inhibit telomerase activity as an off-target effect, although a limited number of studies have reported conflicting findings.
Discussion:
FPF patients with HIV or those receiving Pre-Exposure Prophylaxis (PrEP) are treated with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs). This class of medications includes molecules such as tenofovir, which may exert an off-target inhibitory effect on telomerase. Through this inhibition, telomeres cannot be elongated, and given the reduced telomerase availability, progressive telomere shortening occurs. In cases of telomerase haploinsufficiency, this inhibition could lead to symptom progression and poorer prognosis.
Conclusion:
These findings suggest that caution may be warranted for patients with genetically confirmed telomere-related FPF who require NRTI therapy, considering the potential off-target effects of these drugs on telomerase. Further clinical and mechanistic studies are needed to clarify whether NRTI exposure influences disease progression and prognosis.
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