The development of BVDU: An odyssey

Area of Science:

• Virology
• Antiviral Drug Development
• Medicinal Chemistry

Background:

• Brivudin ((E)-5-(2-bromovinyl)-2'-deoxyuridine, BVDU) is a primary treatment for varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1).
• BVDU's efficacy relies on viral thymidine kinase phosphorylation and it inhibits viral DNA polymerase.
• A critical contraindication for BVDU involves concurrent use with 5-fluorouracil (FU) due to potential toxicity enhancement.

Purpose of the Study:

• To introduce and evaluate a novel bicyclic nucleoside analogue (BCNA), Cf-1743, as a potential VZV therapeutic.
• To compare the antiviral potency of Cf-1743 against BVDU.
• To assess Cf-1743's interaction with 5-fluorouracil (FU) metabolism.

Main Methods:

• In vitro assays to determine antiviral activity against VZV.
• Enzyme inhibition studies assessing viral DNA polymerase activity.
• Pharmacokinetic and drug interaction studies evaluating the effect on 5-FU catabolism.

Main Results:

• Cf-1743 demonstrated superior inhibition of VZV replication compared to BVDU.
• The active form of Cf-1743, FV-100 (Fermavir), is orally bioavailable.
• Crucially, Cf-1743 does not interfere with the catabolism of 5-fluorouracil (FU), unlike BVDU.

Conclusions:

• Cf-1743 represents a potent new antiviral agent for VZV infections.
• Its favorable drug interaction profile and oral bioavailability make it a promising candidate for clinical development.
• Cf-1743 offers a safer alternative to BVDU, particularly for patients requiring concurrent FU treatment.