Synthesis and anti-herpetic activity of phosphoramidate ProTides

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Delivery

Background:

• Nucleoside monophosphate delivery into cells is challenging.
• The phosphoramidate ProTide approach has shown clinical success for prodrug delivery.
• Thymidine kinase (TK) dependence limits the efficacy of some nucleoside analogues.

Purpose of the Study:

• To synthesize and evaluate phosphoramidate ProTides designed to overcome TK dependence.
• To assess the antiviral activity of novel phosphoramidate derivatives against herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV).

Main Methods:

• Synthesis of phosphoramidate ProTides derived from (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and deazapurine nucleosides.
• Evaluation of antiviral activity in cell cultures, including against TK-deficient virus strains.

Main Results:

• Phosphoramidate derivatives of BVDU showed anti-HSV-1 and anti-VZV activity but lost potency against TK-deficient strains.
• 7-deazaadenine nucleoside phosphoramidates exhibited weak antiviral activity against VZV.
• Intracellular nucleotide delivery via these phosphoramidates was partially successful.
• No compound prodrugs demonstrated superior antiviral activity compared to their parent drugs.

Conclusions:

• Phosphoramidate ProTides can facilitate intracellular delivery of nucleoside analogues.
• The ProTide approach did not fully overcome TK dependence for the tested compounds.
• Further optimization is needed to develop potent antiviral prodrugs that bypass TK deficiency.