β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU) prevents varicella-zoster virus replication in a SCID-Hu mouse model and does not interfere with 5-fluorouracil catabolism.

•l-BHDU and its derivatives were effective against varicella-zoster virus in vitro and in vivo.•Unlike brivudine, l-BHDU did not interfere with 5-FU metabolism.•l-BHDU antagonized the antiviral activity of ACV and BVdU in drug combination studies.•l-BHDU and valyl-l-BHDU were well tolerated and potent in the SCID-Hu mouse model of VZV replication.