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Viruses Jan 2022The virus (VZV) or human herpes virus 3 is a neurotropic human alpha herpes virus responsible for chickenpox/varicella and shingles/ (HZ). This review will focus on HZ.... (Review)
Review
The virus (VZV) or human herpes virus 3 is a neurotropic human alpha herpes virus responsible for chickenpox/varicella and shingles/ (HZ). This review will focus on HZ. Since HZ is secondary to varicella, its incidence increases with age. In children and youngsters, HZ is rare and associated to metabolic and neoplastic disorders. In adults, advanced age, distress, other infections (such as AIDS or COVID-19), and immunosuppression are the most common risk factors. HZ reactivation has recently been observed after COVID-19 vaccination. The disease shows different clinical stages of variable clinical manifestations. Some of the manifestations bear a higher risk of complications. Among the possible complications, postherpetic neuralgia, a chronic pain disease, is one of the most frequent. HZ vasculitis is associated with morbidity and mortality. Renal and gastrointestinal complications have been reported. The cornerstone of treatment is early intervention with acyclovir or brivudine. Second-line treatments are available. Pain management is essential. For (secondary) prophylaxis, currently two HZV vaccines are available for healthy older adults, a live attenuated VZV vaccine and a recombinant adjuvanted VZV glycoprotein E subunit vaccine. The latter allows vaccination also in severely immunosuppressed patients. This review focuses on manifestations of HZ and its management. Although several articles have been published on HZ, the literature continues to evolve, especially in regard to patients with comorbidities and immunocompromised patients. VZV reactivation has also emerged as an important point of discussion during the COVID-19 pandemic, especially after vaccination. The objective of this review is to discuss current updates related to clinical presentations, complications, and management of HZ.
Topics: Disease Management; Herpes Zoster; Herpesvirus 3, Human; Herpesvirus Vaccines; Humans; Immunocompromised Host; Incidence; Latent Infection; Morbidity; Neuralgia, Postherpetic; Risk Factors; Vaccination; Vaccines, Synthetic
PubMed: 35215786
DOI: 10.3390/v14020192 -
Molecules (Basel, Switzerland) Feb 2021Varicella-zoster virus (VZV), a common and ubiquitous human-restricted pathogen, causes a primary infection (varicella or chickenpox) followed by establishment of... (Review)
Review
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.
Topics: Antiviral Agents; Encephalitis, Varicella Zoster; Herpesvirus 3, Human; Humans; Microbial Sensitivity Tests; Pyrimidine Nucleosides
PubMed: 33672709
DOI: 10.3390/molecules26041132 -
Acta Pharmaceutica Sinica. B Jan 2020Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the... (Review)
Review
Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the xenobiotic, xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism.
PubMed: 31998605
DOI: 10.1016/j.apsb.2019.12.001 -
The Korean Journal of Pain Jan 2023Herpes zoster (HZ) is a common disease in the aging population and immunocompromised individuals, with a lifetime risk of 20%-30% that increases with age. HZ is caused... (Review)
Review
Herpes zoster (HZ) is a common disease in the aging population and immunocompromised individuals, with a lifetime risk of 20%-30% that increases with age. HZ is caused by reactivation of the varicella-zoster virus (VZV), which remains latent in the spinal dorsal root ganglia and cranial sensory ganglia after resolution of the primary VZV infection. The main focus of HZ management is rapid recovery from VZV infection as well as the reduction and prevention of zoster-associated pain (ZAP) and postherpetic neuralgia (PHN). The use of antivirals against VZV is essential in the treatment of HZ. However, limited antivirals are only licensed clinically for the treatment of HZ, including acyclovir, valacyclovir, famciclovir, brivudine, and amenamevir. Fortunately, some new antivirals against different types of have been investigated and suggested as novel drugs against VZV. Therefore, this review focuses on discussing the difference in efficacy and safety in the currently licensed antivirals for the treatment of HZ, the applicability of future novel antivirals against VZV, and the preventive or therapeutic effects of these antivirals on ZAP or PHN.
PubMed: 36573010
DOI: 10.3344/kjp.22391 -
Antiviral Chemistry & Chemotherapy 2023Brivudin, (()-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) can be considered the gold standard for the treatment of varicella-zoster virus (VZV) infections, such as herpes... (Review)
Review
Brivudin, (()-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) can be considered the gold standard for the treatment of varicella-zoster virus (VZV) infections, such as herpes zoster (shingles). It is available for clinical use in most European countries (except for the UK) and over the whole world (except for the US and Canada). Besides VZV its activity spectrum also includes various other herpesviruses, such as herpes simplex virus type 1 (HSV-1). Its activity against VZV and HSV-1 depends on phosphorylation by the virus-encoded thymidine kinase (TK). In its active form (BVDU TP or BVDU 5'-triphosphate), it can act as both substrate and inhibitor of the viral (i.e., HSV-1) DNA polymerase. It has proven to be effective against herpes zoster, including post-herpetic neuralgia (PHN). It is contra-indicated in patients concomitantly treated by 5-fluorouracil (FU), since its degradation product, ()-5-(2-bromovinyl)uracil, is inhibitory to the catabolism of FU, which may enhance the toxicity of the latter. A new compound, the bicyclic nucleoside analogue (BCNA) Cf-1743, has been described, which is a more potent inhibitor of VZV replication than BVDU and which does not interfere with the catabolism of FU. It is applicable orally, as its 5'-valine ester FV-100 (Fermavir), but has not (yet) been marketed for clinical use.
Topics: Humans; Antiviral Agents; Bromodeoxyuridine; Herpesvirus 3, Human; Herpes Zoster; Herpesvirus 1, Human; Fluorouracil; Thymidine Kinase
PubMed: 36710501
DOI: 10.1177/20402066231152971 -
BioRxiv : the Preprint Server For... Jun 2023Chemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and...
Chemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and development of drug candidates in models that more accurately reflect nutrient availability in human biofluids may help in addressing this major challenge. Here we performed high-throughput screens in conventional versus Human Plasma-Like Medium (HPLM). Sets of conditional anticancer compounds span phases of clinical development and include non-oncology drugs. Among these, we characterize a unique dual-mechanism of action for brivudine, an agent otherwise approved for antiviral treatment. Using an integrative approach, we find that brivudine affects two independent targets in folate metabolism. We also traced conditional phenotypes for several drugs to the availability of nucleotide salvage pathway substrates and verified others for compounds that seemingly elicit off-target anticancer effects. Our findings establish generalizable strategies for exploiting conditional lethality in HPLM to reveal therapeutic candidates and mechanisms of action.
PubMed: 37333068
DOI: 10.1101/2023.06.04.543621 -
Antiviral Chemistry & Chemotherapy Jan 2013This review article focuses on the anti-herpesvirus agents effective against herpes simplex virus, varicella-zoster virus and cytomegalovirus, which have either been... (Review)
Review
This review article focuses on the anti-herpesvirus agents effective against herpes simplex virus, varicella-zoster virus and cytomegalovirus, which have either been licensed for clinical use (idoxuridine, trifluridine, brivudin, acyclovir, valaciclovir, valganciclovir, famciclovir and foscarnet) or are under clinical development (CMX001 [the hexadecyloxypropyl prodrug of cidofovir], the helicase-primase inhibitor BAY 57-1293 [now referred to as AIC316], FV-100 [the valine ester of Cf 1743] and the terminase inhibitor letermovir [AIC246]).
Topics: Animals; Antiviral Agents; Cytomegalovirus; Herpesviridae Infections; Herpesvirus 3, Human; Humans; Simplexvirus
PubMed: 23343513
DOI: 10.3851/IMP2533 -
The Cochrane Database of Systematic... Jan 2015Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis which, though usually self-limiting, may persist or progress without treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis which, though usually self-limiting, may persist or progress without treatment.
OBJECTIVES
To compare the relative effectiveness of antiviral agents, interferon, and corneal debridement in the treatment of HSV epithelial keratitis.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 12), PubMed (January 1946 to 31 December 2014), EMBASE (January 1980 to 31 December 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to 31 December 2014), System for Information on Grey Literature in Europe (OpenGrey) (January 1995 to 31 December 2014), BIOSIS (January 1926 to 5 May 2014), Scopus (January 1966 to 31 December 2014), Japan Science and Technology Institute (J-Global) (January 1975 to 31 December 2014), China National Knowledge Infrastructure (CNKI) (January 1979 to 31 December 2014), British Library's Electronic Table of Contents (Zetoc) (January 1993 to 7 May 2014). We looked for trials listed on the the metaRegister of Controlled Trials (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en), Chinese Clinical Trial Registry, the U.S. Food and Drug Administration (FDA) (www.fda.gov/), National Institute for Health and Clinical Excellence (NICE) (www.
EVIDENCE
nhs.uk) and the European Medicines Agency (EMA) (www.ema.europa.eu/ema/) as of 31 December 2014. There were no language or date restrictions in the search for trials. We also culled literature digests and conference proceedings as of 15 April 2014. There were no language or date restrictions in the search for trials.
SELECTION CRITERIA
Randomised and quasi-randomised trials of HSV dendritic or geographic epithelial keratitis were included that reported the proportion of eyes healed at one week, two weeks, or both after enrolment.
DATA COLLECTION AND ANALYSIS
We tabulated data on study characteristics, risk of bias, and outcomes and used direct comparisons to estimate a risk ratio (RR) and, when feasible, a hazard ratio (HR) with a 95% confidence interval (CI). Heterogeneity was assessed by an inconsistency index. A multiple treatment comparison meta-analysis consolidated direct and indirect comparisons of relative healing at 14 days.
MAIN RESULTS
One hundred thirty-seven studies involving 8333 eyes met the inclusion criteria. Placebo-controlled studies were heterogeneous in comparison with idoxuridine (RR 1.74; 95% CI 1.03 to 2.91) and few in number for vidarabine (RR 1.81; 95% CI 1.09 to 3.01), interferon (RR 1.32; 95% CI 1.06 to 1.64), and debridement. Vidarabine (RR 1.13; 95% CI 1.02 to 1.25), trifluridine (RR 1.30; 95% CI 1.18 to 1.43), acyclovir (RR 1.23; 95% CI 1.14 to 1.34), and brivudine (RR 1.34; 95% CI 1.18 to 1.51) were more effective than idoxuridine. Trifluridine (RR 1.17; 95% CI 1.03 to 1.32) and acyclovir (RR 1.11; 95% CI 1.03 to 1.19) were more effective than vidarabine. No significant differences in healing emerged among trifluridine, acyclovir, brivudine, and foscarnet although few studies compared brivudine or foscarnet with other antivirals. Any potential advantage of ganciclovir compared to acyclovir was mitigated by study heterogeneity and possible publication bias. Only one study evaluated the joint use of two topical antivirals. In a limited number of studies, oral acyclovir (RR 0.92; 95% CI 0.79 to 1.07) or the combination of oral acyclovir with a topical antiviral (RR 1.36; 95% CI 0.68 to 2.74) appeared as effective as a single topical antiviral agent. Compared to topical antiviral monotherapy, the combination of an antiviral with either interferon or debridement had inconsistent effects on expediting healing and improving outcome.
AUTHORS' CONCLUSIONS
Placebo-controlled studies of HSV epithelial keratitis are limited to superseded interventions. Trifluridine and acyclovir are more effective than idoxuridine or vidarabine and similar in therapeutic effectiveness. Brivudine and foscarnet do not substantially differ in effectiveness from trifluridine or acyclovir. Ganciclovir is at least as effective as acyclovir. The addition of interferon to a nucleoside antiviral agent and the combination of debridement with antiviral treatment need to be further assessed to substantiate any possible advantage in healing.
Topics: Administration, Oral; Administration, Topical; Antiviral Agents; Combined Modality Therapy; Debridement; Humans; Interferons; Keratitis, Herpetic; Randomized Controlled Trials as Topic
PubMed: 25879115
DOI: 10.1002/14651858.CD002898.pub5 -
EMBO Molecular Medicine Dec 2022The majority of colorectal cancers (CRCs) present with early mutations in tumor suppressor gene APC. APC mutations result in oncogenic activation of the Wnt pathway,...
The majority of colorectal cancers (CRCs) present with early mutations in tumor suppressor gene APC. APC mutations result in oncogenic activation of the Wnt pathway, which is associated with hyperproliferation, cytoskeletal remodeling, and a global increase in mRNA translation. To compensate for the increased biosynthetic demand, cancer cells critically depend on protein chaperones to maintain proteostasis, although their function in CRC remains largely unexplored. In order to investigate the role of molecular chaperones in driving CRC initiation, we captured the transcriptomic profiles of murine wild type and Apc-mutant organoids during active transformation. We discovered a strong transcriptional upregulation of Hspb1, which encodes small heat shock protein 25 (HSP25). We reveal an indispensable role for HSP25 in facilitating Apc-driven transformation, using both in vitro organoid cultures and mouse models, and demonstrate that chemical inhibition of HSP25 using brivudine reduces the development of premalignant adenomas. These findings uncover a hitherto unknown vulnerability in intestinal transformation that could be exploited for the development of chemopreventive strategies in high-risk individuals.
Topics: Animals; Mice; Transcriptome; Up-Regulation
PubMed: 36321561
DOI: 10.15252/emmm.202216194 -
PloS One 2015Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate...
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.
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 2.9 Å. BVDUP binds similarly as dUMP in the TSHS but it induces a closed conformation of the active site. The structure supports that the 5-bromovinyl substituent on BVDUP is likely to inhibit TSVZV by preventing the transfer of a methylene group from its cofactor and the subsequent formation of dTMP. The interactions between TSVZV and BVDUP are consistent with that TSVZV is indeed a target of brivudine in vivo. The work also provided the structural basis for rational design of more specific TSVZV inhibitors.
Topics: Antiviral Agents; Apoenzymes; Binding Sites; Bromodeoxyuridine; Herpesvirus 3, Human; Humans; Models, Molecular; Phosphorylation; Protein Binding; Protein Conformation; Thymidylate Synthase
PubMed: 26630264
DOI: 10.1371/journal.pone.0143947