Tenofovir is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. While tenofovir can lower the amount of HIV and hepatitis B virus in the blood, it does not provide a cure for either condition. This medication helps manage these chronic conditions by reducing the viral load and supporting the immune system.
Chemical Foundation of Tenofovir
Tenofovir is classified as a nucleotide analog reverse-transcriptase inhibitor (NtRTI). This means it is a synthetic compound designed to mimic the natural building blocks of DNA. Specifically, tenofovir is an acyclic analog of deoxyadenosine monophosphate. Its core structure includes a modified adenine base and an acyclic (open-chain) phosphonate group. The absence of a complete sugar ring distinguishes tenofovir from a nucleoside.
The original tenofovir molecule had limited cell penetration and poor oral absorption. To overcome these challenges, prodrug versions were developed. These chemical modifications enhance the oral absorption of tenofovir by masking the negative charges of its phosphonic acid group.
How Tenofovir’s Structure Disables Viruses
Tenofovir’s unique chemical structure allows it to interfere with viral replication. Once absorbed into the body, tenofovir is converted into its active form, tenofovir diphosphate (TFV-DP), through a process called phosphorylation. This active form then competes with natural deoxyadenosine triphosphate (dATP), a building block required for viral DNA synthesis.
Viral enzymes, such as HIV reverse transcriptase and hepatitis B virus (HBV) DNA polymerase, mistakenly incorporate tenofovir diphosphate into the growing viral DNA chain. Because tenofovir lacks a specific hydroxyl group that is necessary for forming the phosphodiester bonds, its incorporation acts as a “chain terminator.” This prevents further DNA synthesis, effectively halting the replication of the virus. The safety of tenofovir stems from its lower affinity for human cellular DNA polymerases compared to viral ones.
Tenofovir’s Structural Adaptations and Their Clinical Significance
Tenofovir’s structure has been adapted into different drug formulations, primarily Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF). Both TDF and TAF are prodrugs of the active tenofovir molecule. TDF, the older formulation, contains disoproxil ester groups that enhance its oral absorption.
TAF represents a newer structural adaptation, featuring an alafenamide group. TAF is designed to be more stable in plasma than TDF and provides higher intracellular levels of the active tenofovir diphosphate in target cells, such as HIV-infected lymphoid cells and HBV-infected hepatocytes. This improved targeted delivery allows for significantly lower systemic exposure to tenofovir with TAF compared to TDF. The reduced systemic levels of tenofovir with TAF lead to a lower risk of potential side effects, such as kidney and bone toxicity, which were more commonly associated with TDF.