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Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity
Sahar Kandil1, Christophe Pannecouque2, Fiona M Chapman1
1School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
Bioorganic & Medicinal Chemistry Letters
|November 5, 2019
Summary
New stavudine (d4T) ProTides with polyfluorinated aryl groups show enhanced activity against HIV-1 and HIV-2. ProTide 5d demonstrates potent antiviral effects and high selectivity, offering a promising advancement in HIV treatment.
Area of Science:
- Medicinal Chemistry
- Virology
- Drug Discovery
Background:
- Human Immunodeficiency Virus (HIV) infection remains a significant global health concern, despite advances in antiretroviral therapies.
- Nucleoside analogues are key in treating viral infections but face limitations in cellular uptake, activation, and metabolism.
- Stavudine (d4T) is a nucleoside analogue used in HIV treatment, but its efficacy can be improved.
Purpose of the Study:
- To synthesize and evaluate novel stavudine (d4T) ProTides incorporating polyfluorinated aryl groups.
- To assess the in vitro antiviral activity of these ProTides against HIV-1 and HIV-2 strains.
- To investigate the impact of fluorination on the potency and selectivity of d4T analogues.
Main Methods:
- Synthesis of novel ProTide derivatives of stavudine (d4T).
- In vitro antiviral assays against HIV-1 (IIIB) and HIV-2 (ROD) strains.
- Evaluation of ProTides in both wild-type and thymidine kinase-deficient (TK-) cells.
- Enzymatic activation studies using carboxypeptidase Y and NMR spectroscopy (31P and 19F).
Main Results:
- ProTide 5d, featuring a meta-substituted pentafluorosulfanyl (3-SF5) aryl group, exhibited significantly enhanced antiviral activity compared to parent d4T.
- ProTide 5d demonstrated low nanomolar potency (IC50 = 30 nM for HIV-1, 36 nM for HIV-2), exceeding d4T by over tenfold.
- ProTide 5d displayed high selectivity indices (SI = 1753 for HIV-1, 1461 for HIV-2), more than double that of d4T.
- Enzymatic activation of ProTide 5d was successfully demonstrated and monitored.
Conclusions:
- The incorporation of polyfluorinated aryl groups, specifically the 3-SF5 moiety in ProTide 5d, substantially improves the antiviral potency and selectivity of stavudine (d4T).
- ProTide 5d represents a promising new class of antiretroviral agents with potential for improved HIV therapy.
- These findings highlight the utility of ProTide technology in overcoming limitations of nucleoside analogues for antiviral drug development.
