Advances and Perspectives in the Management of Varicella-Zoster Virus Infections

Abstract

Varicella-zoster virus (VZV), a common and ubiquitous human-restricted pathogen, causes a primary infection (varicella or chickenpox) followed by establishment of latency in sensory ganglia. The virus can reactivate, causing herpes zoster (HZ, shingles) and leading to significant morbidity but rarely mortality, although in immunocompromised hosts, VZV can cause severe disseminated and occasionally fatal disease. We discuss VZV diseases and the decrease in their incidence due to the introduction of live-attenuated vaccines to prevent varicella or HZ. We also focus on acyclovir, valacyclovir, and famciclovir (FDA approved drugs to treat VZV infections), brivudine (used in some European countries) and amenamevir (a helicase-primase inhibitor, approved in Japan) that augur the beginning of a new era of anti-VZV therapy. Valnivudine hydrochloride (FV-100) and valomaciclovir stearate (in advanced stage of development) and several new molecules potentially good as anti-VZV candidates described during the last year are examined. We reflect on the role of antiviral agents in the treatment of VZV-associated diseases, as a large percentage of the at-risk population is not immunized, and on the limitations of currently FDA-approved anti-VZV drugs. Their low efficacy in controlling HZ pain and post-herpetic neuralgia development, and the need of multiple dosing regimens requiring daily dose adaptation for patients with renal failure urges the development of novel anti-VZV drugs.

Keywords: HZ; amenamevir; anti-VZV drugs; chickenpox; helicase-primase inhibitors; nucleoside analogues; shingles; valnivudine hydrochloride (FV-100); valomaciclovir stearate; varicella-zoster virus (VZV).

Figure 1

Activation and mechanism of action of (A) acyclovir (ACV) and penciclovir (PCV) and (B) cidofovir (CDV) and foscarnet (PFA). Valacyclovir (VACV), the oral prodrug of ACV, has improved absorption compared to ACV because of a stereo-selective transporter in the human intestine by dipeptide transporters followed by rapid and efficient hydrolysis to ACV by estereases found in the gut lumen, intestinal wall and liver. Famciclovir (FAM), the oral prodrug of PCV, follows first deacetylation at the 3 and 4 positions of the acyclic side chain and then oxidation at the 6 position of the purine ring yielding the active metabolite, PCV. The conversion to the monophosphate (MP) forms of ACV and PCV is carried out by the viral thymidine kinase (TK). The cellular enzyme guanosine monophosphate kinase or guanylate kinase (GMP) performs further phosphorylation to the diphosphate (DP) forms. Following conversion to their triphosphate (TP) forms by the cellular nucleoside 5′-diphosphate (NDP) kinase, the active metabolites inhibit viral DNA polymerases because they act as competitive inhibitors of the natural substrate (i.e., deoxyguanosine triphosphate, dGTP) and/or as alternative substrates when incorporated into the growing DNA chain. Incorporation of ACV-TP into the growing DNA chain results in chain termination due to the lack of an OH at the 5′ position. PCV-TP is not an obligate chain terminator due to the presence of an OH at the 5′ position and its incorporation results in slowdown of DNA chain elongation. The acyclic nucleotide analogue cidofovir (CDV) does not require activation by a virus-encoded enzyme for activation as the molecule already carries a phosphonate bond. In contrast to the O-P linkage (phosphate), the CH2-P-bond (phosphonate) is resistant to phosphodiesterase and phosphatase hydrolysis. Therefore, acyclic nucleoside phosphonates (ANPs), such as CDV, which mimic the nucleoside monophosphates, can bypass the initial enzymatic phosphorylation by viral kinases. Similar to a nucleoside monophosphate, a nucleoside phosphonate is further phosphorylated by cellular nucleotide kinases. The conversion of CDV to its active metabolite, i.e., CDV-diphosphate (CDVpp) is performed by cellular kinases [UMP/CMP kinase 1 (UMP/CMPK-1) and 5′-diphosphate (NDP) kinase]. CDV-DP, recognized by the viral DNA polymerase, will then block DNA synthesis by acting as competitive inhibitor with respect of the natural substrate dCTP or as alternative substrate leading to incorporation into the growing DNA. Chain termination occurs when two consecutive CDVpp’s are incorporated. CDVp-choline is regarded as an intracellular reservoir of CDVp and CDVpp. Foscarnet (PFA, phosphonoformic acid) does not require any activation by viral or cellular kinases and directly interacts with the viral DNA polymerase. PFA binds to the pyrophosphate exchange site of the viral DNA polymerase, blocking the release of pyrophosphate from the terminal nucleoside triphosphate and thus, impeding the formation of the 3′-5′-phosphodiester linkage essential for viral DNA elongation.

Figure 2

Activation, mechanism of action and catabolism of brivudine (BVDU). The VZV thymidine kinase (TK) as well as HSV-1 TK, display both thymidine kinase and thymidylate (dTMP) kinase activities, responsible for the activation of BVDU to the monophosphate (BVDU-MP) and diphosphate (BVDU-DP) forms, respectively. The conversion of BVDU-DP to the active triphosphate metabolite (BVDU-TP) is carried out by the cellular nucleoside 5′-diphosphate (NDP) kinase. BVDU-TP is recognized by DNA polymerases as an alternative substrate and is incorporated into the DNA molecule via internucleotide linkages. Pyrimidine nucleoside analogues, such as BVDU and BVaraU, can be degraded by pyrimidine catabolic enzymes (such as uridine phosphorylase or thymidine phosphorylase (TPase) leading to their free base metabolites without antiviral activity. BVDU cannot be administered together with 5-flurouracil or its prodrug capecitabine because BVU (the product formed following BVDU degradation by the thymidine phsophorylase), is a potent inhibitor of dihydropyrimidine dehydrogenase. This enzyme is needed for the first step in the catabolic pathway of pyrimidines and for 5-fluorouracil degradation and hence co-administration of 5-fluorouracil and brivudine leads to increased exposure to 5-fluorouracil.

Figure 3

Anti-VZV drugs in advanced development. Chemical structures of CF-1743 and its prodrug valnivudine hydrochloride (FV-100) and of omaciclovir (H2G) and its prodrug valomaciclovir stearate.

Figure 4

Activation, mechanism of action and catabolism of bicyclic nucleoside analogues (BCNAs). VZV TK converts BCNA’s to the mono- and diphosphate forms although whether there is conversion to the triphosphate form and which is the active metabolite and mechanism of action remain unclear to date. Striking differences between BCNAs and BVDU exist regarding their catabolic pathways. In contrast to BVDU, human TPases do not recognize BCNA’s as substrates and the free bases of BCNAs do not inhibit human DPD (dihydropyrimidine dehydrogenases) and thereof, there is a normal metabolism of Capecitabine/5-fluorouracyl. Dashed grey arrows indicate lack of activation.