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Review
. 2023 Nov 9;15(11):2234.
doi: 10.3390/v15112234.

The Application of Prodrugs as a Tool to Enhance the Properties of Nucleoside Reverse Transcriptase Inhibitors

Lívia da Rocha Fernandes  1 , Juliana Romano Lopes  1 , Andressa Francielli Bonjorno  1 , João Lucas Bruno Prates  1 , Cauê Benito Scarim  1 , Jean Leandro Dos Santos  1
Affiliations
Review

The Application of Prodrugs as a Tool to Enhance the Properties of Nucleoside Reverse Transcriptase Inhibitors

Lívia da Rocha Fernandes et al. Viruses. .

Abstract

Antiretroviral Therapy (ART) is an effective treatment for human immunodeficiency virus (HIV) which has transformed the highly lethal disease, acquired immunodeficiency syndrome (AIDS), into a chronic and manageable condition. However, better methods need to be developed for enhancing patient access and adherence to therapy and for improving treatment in the long term to reduce adverse effects. From the perspective of drug discovery, one promising strategy is the development of anti-HIV prodrugs. This approach aims to enhance the efficacy and safety of treatment, promoting the development of more appropriate and convenient systems for patients. In this review, we discussed the use of the prodrug approach for HIV antiviral agents and emphasized nucleoside reverse transcriptase inhibitors. We comprehensively described various strategies that are used to enhance factors such as water solubility, bioavailability, pharmacokinetic parameters, permeability across biological membranes, chemical stability, drug delivery to specific sites/organs, and tolerability. These strategies might help researchers conduct better studies in this field. We also reported successful examples from the primary therapeutic classes while discussing the advantages and limitations. In this review, we highlighted the key trends in the application of the prodrug approach for treating HIV/AIDS.

Keywords: AIDS; HIV; codrugs; medicinal chemistry; new drugs; nucleoside reverse transcriptase inhibitors (NRTIs); prodrugs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structural representation of zidovudine prodrugs.
Figure 2
Figure 2
A diagrammatic representation of the prodrug approach to improve TFV properties. TDF can improve pharmacokinetic properties, as it can cross the biological membrane. Enzymatic or chemical activation leads to a TFV form that is then converted to TFV-DP by the action of the kinases.
Figure 3
Figure 3
The proposed mode of action of ProTides. ProTide can efficiently cross the cell membrane and is enzymatically cleaved off in the intracellular region, releasing the free nucleoside monophosphate. TVF and TAF are examples of the ProTide approach.
Figure 4
Figure 4
Structural modifications led to the obtaining of derivatives of TAF (7) and TVF (8 and 9). Red dots represents lypophilic subunits [39].
Figure 5
Figure 5
Lipid–drug conjugate metabolism. Lipophilic drugs exert their effects until they reach systemic circulation.
Figure 6
Figure 6
Structural representation of tenofovir prodrugs. Red dots highlights some of the modifications performed in the drugs.
Figure 7
Figure 7
Structural representation of lamivudine prodrugs.
Figure 8
Figure 8
Structural representation of stavudine prodrugs.
Figure 9
Figure 9
Drug release mechanism of cycloSal prodrugs. The cyclic group undergoes cleavage through chemically induced processes in two different regions as presented by (a) and (b).
Figure 10
Figure 10
Structural representation of stavudine prodrugs, using the DiPPro and TriPPPro approaches.
Figure 11
Figure 11
Structural representation of emtricitabine prodrugs.
Figure 12
Figure 12
Structural representation of abacavir prodrugs.
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