1.Spectrum of activity and mechanisms of resistance of various nucleoside derivatives against gammaherpesviruses.
Coen N1, Duraffour S1, Topalis D1, Snoeck R1, Andrei G2. Antimicrob Agents Chemother. 2014 Dec;58(12):7312-23. doi: 10.1128/AAC.03957-14. Epub 2014 Sep 29.
The susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various nucleoside analogs was investigated in this work. Besides examining the antiviral activities and modes of action of antivirals currently marketed for the treatment of alpha- and/or betaherpesvirus infections (including acyclovir, ganciclovir, penciclovir, foscarnet, and brivudin), we also investigated the structure-activity relationship of various 5-substituted uridine and cytidine molecules. The antiviral efficacy of nucleoside derivatives bearing substitutions at the 5 position was decreased if the bromovinyl was replaced by chlorovinyl. 1-β-D-Arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), a nucleoside with an arabinose configuration of the sugar ring, exhibited no inhibitory effect against rhadinoviruses but was active against EBV. On the other hand, the fluoroarabinose cytidine analog 2'-fluoro-5-iodo-aracytosine (FIAC) showed high selectivity indices against gammaherpesviruses that were comparable to those of brivudin.
2.Comparison of Famciclovir, Valaciclovir, and Brivudine Treatments in Adult Immunocompetent Patients With Herpes Zoster.
Yaldiz M1, Solak B, Kara RO, Cosansu N, Erdem MT. Am J Ther. 2016 Jan 20. [Epub ahead of print]
Herpes zoster (HZ) is a common disease characterized by the recurrence of varicella zoster, that stays dormant in sensory ganglia. The primary goal of this study was to compare efficiencies of famciclovir, valaciclovir, and brivudine in terms of pain relief in HZ patients. Records of patients who were admitted to the Dermatology Clinic of our hospital due to acute HZ between the years 2012 and 2014 were retrospectively analyzed. Treatment decisions were at the discretion of caring physicians as valaciclovir (VACV), famciclovir (FCV), and brivudine (BRV) based on the clinical observations. BRV, FCV, and VACV were effective in treating pain in acute HZ. There was no significant difference between mild and moderate HZ patients. In severe cases, a significant reduction in intensity of pain was observed on day 3 in the BRV group, on day 7 in the FCV group, and at 2-3 weeks in the VACV group. There were no significant side effects observed in any of the groups.
3.Structure of the Varicella Zoster Virus Thymidylate Synthase Establishes Functional and Structural Similarities as the Human Enzyme and Potentiates Itself as a Target of Brivudine.
Hew K1, Dahlroth SL1, Veerappan S1, Pan LX1, Cornvik T1, Nordlund P1,2,3. PLoS One. 2015 Dec 2;10(12):e0143947. doi: 10.1371/journal.pone.0143947. eCollection 2015.
Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate synthase (TS), which is the sole enzyme that produces dTMP from dUMP de novo. To study substrate binding, the complex structure of TSVZV with dUMP was determined to a resolution of 2.9 Å. In the absence of a folate co-substrate, dUMP binds in the conserved TS active site and is coordinated similarly as in the human encoded TS (TSHS) in an open conformation. The interactions between TSVZV with dUMP and a cofactor analog, raltitrexed, were also studied using differential scanning fluorimetry (DSF), suggesting that TSVZV binds dUMP and raltitrexed in a sequential binding mode like other TS. The DSF also revealed interactions between TSVZV and in vitro phosphorylated brivudine (BVDUP), a highly potent anti-herpesvirus drug against VZV infections. The binding of BVDUP to TSVZV was further confirmed by the complex structure of TSVZV and BVDUP solved at a resolution of 2.
4.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.
De C1, Liu D2, Zheng B3, Singh US4, Chavre S5, White C6, Arnold RD7, Hagen FK8, Chu CK9, Moffat JF10. Antiviral Res. 2014 Oct;110:10-9. doi: 10.1016/j.antiviral.2014.07.007. Epub 2014 Jul 19.
The alphaherpesvirus varicella-zoster virus (VZV) causes chickenpox and shingles. Current treatments are acyclovir (ACV) and its derivatives, foscarnet and brivudine (BVdU). Additional antiviral compounds with increased potency and specificity are needed to treat VZV, especially to treat post-herpetic neuralgia. We evaluated β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU, 1) and 5'-O-valyl-l-BHDU (2) in three models of VZV replication: primary human foreskin fibroblasts (HFFs), skin organ culture (SOC) and in SCID-Hu mice with skin xenografts. The efficacy of l-BHDU in vivo and its drug-drug interactions were previously not known. In HFFs, 200μM l-BHDU was noncytotoxic over 3days, and l-BHDU treatment reduced VZV genome copy number and cell to cell spread. The EC50 in HFFs for l-BHDU and valyl-l-BHDU were 0.22 and 0.03μM, respectively. However, l-BHDU antagonized the activity of ACV, BVdU and foscarnet in cultured cells.