Joachim Bugert | Cardiff University (original) (raw)

Papers by Joachim Bugert

ACS Medicinal Chemistry Letters, 2020

Antiviral Research, 2008

Acyclovir and its prodrug valacyclovir are currently the treatments of choice for herpes simplex ... more Acyclovir and its prodrug valacyclovir are currently the treatments of choice for herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Intracellular conversion of acyclovir to its active triphosphate form is severely limited by the first phosphorylation step, which is carried out by a herpes virus encoded thymidine kinase (Elion et al., 1977). Further conversions to the di- and triphosphate are mediated by cellular guanosine monophosphate kinase and nucleoside diphosphate kinase respectively. Importantly, the activation of the compound by the viral nucleoside kinase is a target for drug resistance in both HSV and VZV strains (Larder et al., 1983). Our phosphoramidate ProTide approach was applied to acyclovir as a means to bypass the limiting step of its activation. However, no significant improvement in antiviral activity was observed (McGuigan et al., 2000). In the present work, a new series of optimised acyclovir ProTides with an enhanced biological profile is reported (Fig. 1).

Pharmaceuticals, 2022

Despite numerous advances in personalized phage therapy, smooth logistics are challenging, partic... more Despite numerous advances in personalized phage therapy, smooth logistics are challenging, particularly for multidrug-resistant Gram-negative bacterial infections requiring high numbers of specific lytic phages. We conducted this study to pave the way for efficient logistics for critically ill patients by (1) closely examining and improving a current pipeline under realistic conditions, (2) offering guidelines for each step, leading to safe and high-quality phage supplies, and (3) providing a tool to evaluate the pipeline’s efficiency. Due to varying stipulations for quality and safety in different countries, we focused the pipeline on all steps up to a required phage product by a cell-free extract system. The first of three study runs included patients with respiratory bacterial infections from four intensive care units, and it revealed a cumulative time of up to 23 days. Ultimately, adjustment of specific set points of the vulnerable components of the pipeline, phage isolation, an...

Virus Genes, 2021

Chikungunya virus (CHIKV) is a (re)emerging arbovirus and the causative agent of chikungunya feve... more Chikungunya virus (CHIKV) is a (re)emerging arbovirus and the causative agent of chikungunya fever. In recent years, CHIKV was responsible for a series of outbreaks, some of which had serious economic and public health impacts in the affected regions. So far, no CHIKV-specific antiviral therapy or vaccine has been approved. This review gives a brief summary on CHIKV epidemiology, spread, infection and diagnosis. It furthermore deals with the strategies against emerging diseases, drug development and the possibilities of testing antivirals against CHIKV in vitro and in vivo. With our review, we hope to provide the latest information on CHIKV, disease manifestation, as well as on the current state of CHIKV vaccine development and post-exposure therapy.

Practical Immunodermatology, 2016

SSRN Electronic Journal, 2021

Abstract: Spike-specific antibodies contribute significantly to the neutralizing activity against... more Abstract: Spike-specific antibodies contribute significantly to the neutralizing activity against SARS-CoV-2 and are important for the therapeutic effect of convalescent plasma. B.1.1.7 is a recently emerged variant of SARS-CoV-2 that has several mutations in the gene encoding for the spike-protein. To assess the potential effect these mutations could have on the neutralizing efficacy of antibodies, we evaluated 96 serum samples from convalescent plasma donors collected before the first occurrence of B.1.1.7 and tested their neutralizing effect on wild-type SARS-CoV-2 and B.1.1.7. We found that B.1.1.7 is more resistant to neutralization by convalescent plasma from patients infected with wild-type SARS-CoV-2 with an overall decrease in neutralizing activity of 47.7%. Thus, the neutralizing effect of convalescent plasma should be determined against the major circulating virus clades whenever possible to ensure the best possible therapeutic effect.

BMC Microbiology, 2021

Background Multidrug-resistant Klebsiella pneumoniae spp. (kp) are emerging agents of severe infe... more Background Multidrug-resistant Klebsiella pneumoniae spp. (kp) are emerging agents of severe infections of the respiratory, urinary tract and wounds that can progress to fatal septicemia. The use of bacteriophages is currently being considered as an effective alternative or adjuvant to antibiotic therapy. Results In this study, we report capsule (K)-typing of 163 carbapenem-resistant Kp (CRKP) isolated 2014–2018 at the Military Hospital of Instruction of Tunis (MHT), Tunisia, by partial amplification and sequencing of the Kp wzi gene. The most prevalent K-type overall was K64 with 50.3% followed by K17 and K27 (22.7 and 11.0%, respectively). K64 Kp strains were most common and associated with increased case/fatality rates, especially at the intensive care unit (ICU). Using a K64 Kp strain we isolated and characterized a lytic Kp phage, vB_KpP_TUN1 (phage TUN1), from wastewater samples of the ICU at the MHT. TUN1 belongs to the Autographiviridae family and specifically digests K64 Kp...

Current Clinical Microbiology Reports, 2021

Purpose of Review The world is currently facing the largest global health crisis since the early ... more Purpose of Review The world is currently facing the largest global health crisis since the early 1900s due to a novel coronavirus. While SARS-CoV-2 infection causes predictable symptoms in COVID-19 patients, including upper respiratory distress and fever, the heterogeneity of manifestations is surprising. This review focuses on direct and indirect causes of myocardial injury in COVID-19 patients and highlights current knowledge, treatment strategies, and outstanding questions in the field. Recent Findings Data are emerging that highlight the extent of cardiovascular involvement in COVID-19 patients, including evidence that SARS-CoV-2 causes myocarditis and increases cardiac risk. The incidence of cardiac injury is much greater in patients with severe disease presentation and those in intensive care. Summary During the past year, COVID-19 patient mortality rates have improved due to tailored pharmacological treatments and patient management strategies that address the unique presentation of symptoms, which will hopefully also reduce the incidence of cardiac injury.

Molecules, 2020

Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health ... more Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against ...

Virus Genes, 2020

The viruses historically implicated or currently considered as candidates for misuse in bioterror... more The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha-and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.

Proceedings, 2020

Here, we present empirical data documenting the siRNA-mediated protection of cells after Zika vir... more Here, we present empirical data documenting the siRNA-mediated protection of cells after Zika virus (ZIKV) infection. siRNAs were designed to target well-conserved sequences across the ZIKV genome. Several delivery technologies were utilized. After the electroporation of 100 nM siRNA into human hepatocyte-derived carcinoma (Huh7) cells, the Feron Zv-2 sequence (specific to the ZIKV NS3 gene) yielded a cell viability of 150.3% ± 7.4% (SEM: n = 4) (p = 0.0004) relative to the cells treated only with the virus (33.9% ± 12%, SEM: n = 4). Furthermore, 100 nM siRNA Feron Zv-4 (specific to ZIKV 3’UTR) resulted in 119.1% ± 11.2% cell viability (SEM: n = 4) relative to the control cells treated with ZIKV (p = 0.0021). The cells were electroporated with siRNA prior to ZIKV infection and viability was monitored four days after this. Additionally, two novel siRNA delivery systems were tested. The first utilized recombinant Bacillus anthracis PA83 (octomer-forming mutants), co-incubated with the...

Future Virology, 2019

Aim: The molluscum contagiosum virus (MCV) expresses several immune evasion molecules that inhibi... more Aim: The molluscum contagiosum virus (MCV) expresses several immune evasion molecules that inhibit activation of NF-κB. Presumably, inhibition of inflammatory responses mediated by NF-κB allows MCV to cause persistent infections. Materials & methods: MC163-IKK-α interactions were detected by immunoprecipitations. Results: Here, we identify a novel MCV inhibitor of NF-κB. Ectopic expression of the MC163 protein resulted in a significant decrease in TNF-α-induced NF-κB activation. However, MC163 had no detectable effect on mitochondrial antiviral-signaling protein-induced activation of the IFN-β-promoter. MC163 dampened NF-κB activation induced via the overexpression of either IKK-α or IKK-β suggesting MC163 targets the IKK complex. Conclusion: Our data highlight a previously unknown function for the MC163 protein and may represent an additional strategy used by MCV to subvert host immune responses.

Viruses, 2019

Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, ... more Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spec...

Current protocols in microbiology, Jan 9, 2017

Molluscum contagiosum virus (MCV) is a common skin pathogen of children and young adults. Infecti... more Molluscum contagiosum virus (MCV) is a common skin pathogen of children and young adults. Infection with MCV causes benign skin tumors in children and young adults and is mostly self-limiting. In contrast to orthopoxviruses, MCV infections tend to take a subacute clinical course but may persist for up to 12 months. Current numbers for MCV seroprevalence in different geographical areas are based on a variety of historical serological methods from complement fixation assays to MCV ELISAs based on purified MCV virions and MC133 antigen expressed in a Semliki Forest Virus expression system. A standardized ELISA for the assessment of MCV seroprevalence would be useful to determine global MCV seroprevalence. The methods described show that polypeptides derived from MCV open reading frames MC084 (residues V123 to R230 and V33 to G117), mc133 (residues M1 to N370), and glutathione S-transferase (GST)-H3L (residues I142 to W251) expressed in E. coli RIL+ as GST fusion proteins can be used to...

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2017

Coadministration of pomegranate rind extract (PRE) and zinc (II) ions has recently been reported ... more Coadministration of pomegranate rind extract (PRE) and zinc (II) ions has recently been reported as a potential new topical treatment for Herpes simplex virus (HSV) infections. In the current work we examined the in vitro topical delivery of punicalagin (major phytochemical of PRE) and zinc from hydrogels across epithelial membranes that can become infected with HSV. Porcine epidermal, buccal and vaginal mucous membranes were excised and mounted in Franz diffusion cells and dosed with a simple hydrogel containing PRE and zinc sulphate (ZnSO4). The permeation of punicalagin and zinc were determined by HPLC and ICPMS respectively; punicalagin was also determined in the basal layers by reverse tape stripping. Receptor phases from the epidermal membrane experiment were also used to challenge HSV-1 in Vero host cells, and ex vivo porcine skin was used to probe COX-2 modulation. Punicalagin and zinc permeated each of the three test membranes, with significantly greater amounts of both del...

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2017

Coadministered pomegranate rind extract (PRE) and zinc (II) produces a potent virucidal activity ... more Coadministered pomegranate rind extract (PRE) and zinc (II) produces a potent virucidal activity against Herpes simplex virus (HSV); however, HSV infections are also associated with localised inflammation and pain. Here, the objective was to determine the anti-inflammatory activity and relative depth penetration of PRE, total pomegranate tannins (TPT) and zinc (II) in skin, ex vivo. PRE, TPT and ZnSO4 were dosed onto freshly excised ex vivo porcine skin mounted in Franz diffusion cells and analysed for COX-2, as a marker for modulation of the arachidonic acid inflammation pathway, by Western blotting and immunohistochemistry. Tape stripping was carried out to construct relative depth profiles. Topical application of PRE to ex vivo skin downregulated expression of COX-2, which was significant after just 6h, and maintained for up to 24h. This was achieved with intact stratum corneum, proving that punicalagin penetrated skin, further supported by the depth profiling data. When PRE and ...

Virology, 2017

Apoptosis is a powerful host cell defense to prevent viruses from completing replication. Poxviru... more Apoptosis is a powerful host cell defense to prevent viruses from completing replication. Poxviruses have evolved complex means to dampen cellular apoptotic responses. The poxvirus, Molluscum Contagiosum Virus (MCV), encodes numerous host interacting molecules predicted to antagonize immune responses. However, the function of the majority of these MCV products has not been characterized. Here, we show that the MCV MC163 protein localized to the mitochondria via an N-terminal mitochondrial localization sequence and transmembrane domain. Transient expression of the MC163 protein prevented mitochondrial membrane permeabilization (MMP), an event central to cellular apoptotic responses, induced by either Tumor Necrosis Factor alpha (TNF-α) or carbonyl cyanide 3-chlorophenylhydrazone (CCCP). MC163 expression prevented the release of a mitochondrial intermembrane space reporter protein when cells were challenged with TNF-α. Inhibition of MMP was also observed in cell lines stably expressin...