Publications by authors named "Mark N Prichard"

Article Synopsis
  • - The study examined cases of mother-to-infant transmission of herpes simplex virus (HSV-2) and found that neonatal herpes is rare despite common exposure, focusing on viral factors that contribute to this transmission
  • - It was discovered that infant isolates had more temperature-independent characteristics and mutations in the viral UL13 protein kinase (UL13-PK) compared to maternal isolates, with a higher prevalence of these mutations occurring shortly after birth
  • - Additionally, the research identified elongation factor 1-delta as a target of UL13-PK, suggesting that mutations in this protein are crucial for the virus's adaptation and successful transmission from mother to infant.
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Human cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes latent asymptomatic infections in healthy individuals but can cause serious infections in immunocompromised people, resulting in increased risk of morbidity and mortality. The current FDA-approved CMV drugs target late stages of the CMV life-cycle. While these drugs are effective in most cases, they have serious drawbacks, including poor oral bioavailability, dose-limiting toxicity, and a low barrier to resistance.

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DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity.

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The substantial impact of acyclic nucleoside phosphonates (ANPs) on human medicine encourages the synthesis of new ANP analogues with a potentially differentiated antiviral spectrum. Herein, we demonstrate the functionalization of the 2-position of the (,)-3-hydroxy-2-(phosphonomethoxy)propyl side-chain of an inactive ANP with a polar cyano group to generate a thymine analogue with selective inhibition of hepatitis B virus (HBV) replication (SI > 302; EC = 0.33 μM), without significant antiretroviral activity.

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Human adenovirus (HAdV) infection is common in the general population and can cause a range of clinical manifestations, among which pneumonia and keratoconjunctivitis are the most common. Although HAdV infections are mostly self-limiting, infections in immunocompromised individuals can be severe. No antiviral drug has been approved for treating adenoviruses.

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Article Synopsis
  • - A new series of 2-oxoimidazolidine derivatives were created and tested for their antiviral effects against BK human polyomavirus type 1 (BKPyV) in laboratory settings.
  • - Two specific compounds, 5 and 4, showed moderate antiviral activity similar to the established drug Cidofovir, with effective concentrations around 5.4 and 5.5 μm, respectively.
  • - While compound 5 had comparable cytotoxicity and selectivity index to Cidofovir, compound 4 was more toxic, leading to a lower selectivity index, indicating that these compounds could be further explored as potential anti-BKPyV treatments.
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More than 14,000 neonates are infected with herpes simplex virus (HSV) annually. Approximately half display manifestations limited to the skin, eyes, or mouth (SEM disease). The rest develop invasive infections that spread to the central nervous system (CNS disease or encephalitis) or throughout the infected neonate (disseminated disease).

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Objective: To determine frequency of hospital-acquired viral respiratory infections (HA-VRI) and associated outcomes in a NICU.

Study Design: Prospective cohort study conducted from 4 October 2016 to 21 March 2017. Infants hospitalized from birth in the NICU had a weekly nasal swab collected for testing using a multiplex PCR assay capable of detecting 16 different respiratory viruses.

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This paper describes an access to new nitrogen-containing heterocyclic triterpenoids by the reaction of 2,3-indolotriterpenoids with ozone and dimethyldioxirane. The oxidation of indolo-fused 28-oxo-allobetulin or methyl platanoate with ozone led to a mixture of a quinolone as the major product and a nine-membered 2,3-seco-2-oxolactam and three different types of spiroindoles as byproducts. The formation of quinolone and 2,3-seco-2-oxolactam derivatives could be explained by the standard 1,3-dipolar cycloaddition of ozone to the C2(3)-double bond of the triterpene core similar to the products observed in the ozonolysis of indoles in the Witkop-Winterfeldt oxidation (WWO).

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The search for new compounds with a broad spectrum of antiviral activity is important and requires the evaluation of many compounds against several distinct viruses. Researchers attempting to develop new antiviral therapies for DNA virus infections currently use a variety of cell lines, assay conditions and measurement methods to determine in vitro drug efficacy, making it difficult to compare results from within the same laboratory as well as between laboratories. In this paper, we describe the assessment of antiviral activity of a set of nucleoside analogs against BK polyomavirus, JC polyomavirus, Epstein-Barr virus, human herpesvirus 6B, and human herpesvirus 8 in an automated 384-well format and utilize qPCR assays to measure the accumulation of viral DNA.

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The search for new compounds with a broad spectrum of antiviral activity is important and requires the evaluation of many compounds against several distinct viruses. Researchers attempting to develop new antiviral therapies for DNA virus infections currently use a variety of cell lines, assay conditions and measurement methods to determine in vitro drug efficacy, making it difficult to compare results from within the same laboratory as well as between laboratories. In this paper we describe a common assay platform designed to facilitate the parallel evaluation of antiviral activity against herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, cytomegalovirus, vaccinia virus, cowpox virus, and adenovirus.

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Background: Recent advances in xenotransplantation have produced organs from pigs that are well tolerated in primate models because of genetic changes engineered to delete major antigens from donor animals. To ensure the safety of human transplant recipients, it will be essential to understand both the spectrum of infectious agents in donor pigs and their potential to be transmitted to immunocompromised transplant recipients. Equally important will be the development of new highly sensitive diagnostic methods for use in the detection of these agents in donor animals and for the monitoring of transplant recipients.

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The recent approval of letermovir marks a new era of therapy for human cytomegalovirus (HCMV) infections, particularly for the prevention of HCMV disease in hematopoietic stem cell transplant recipients. For almost 30 years ganciclovir has been the therapy of choice for these infections and by today's standards this drug exhibits only modest antiviral activity that is often insufficient to completely suppress viral replication, and drives the selection of drug-resistant variants that continue to replicate and contribute to disease. While ganciclovir remains the therapy of choice, additional drugs that inhibit novel molecular targets, such as letermovir, will be required as highly effective combination therapies are developed not only for the treatment of immunocompromised hosts, but also for congenitally infected infants.

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Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, AdV can cause serious infection in severely immunosuppressed individuals, especially pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, where mortality rates are up to 80% with disseminated disease. Despite the seriousness of AdV disease, there are no drugs approved specifically to treat AdV infections.

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Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination.

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Article Synopsis
  • The study explored the relationship between plaque reduction (PR) and virus yield reduction (VYR) assays for analyzing drug interactions in antiviral experiments, particularly focusing on synergy measurements using MacSynergy II software.
  • Results indicated that the Volume of Synergy (VS) could differ significantly between PR and VYR assays, with cidofovir and 6-azauridine showing strong synergy in PR (VS = 265) but weak synergy in VYR (VS = 37).
  • The findings suggest that VS values derived from logarithmic data may underestimate synergy and antagonism, proposing specific thresholds for determining strong interactions based on different measurement scales.
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Human papillomavirus (HPV) high-risk genotypes such as HPV-16 and HPV-18 cause the majority of anogenital tract carcinomas, including cervical cancer, the second most common malignancy in women worldwide. Currently there are no approved antiviral agents that reduce or eliminate HPV and reverse virus-associated pathology. We synthesized and evaluated several alkoxyalkyl acyclic nucleoside phosphonate diesters and identified octadecyloxyethyl benzyl 9-[(2-phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG) as an active compound which strongly inhibited transient amplification of HPV-11, -16, and -18 origin-containing plasmid DNA in transfected cells at concentrations well below its cytotoxic concentrations.

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Human polyomaviruses are generally latent but can be reactivated in patients whose immune systems are suppressed. Unfortunately, current therapeutics for diseases associated with polyomaviruses are non-specific, have undefined mechanisms of action, or exacerbate the disease. We previously reported on a class of dihydropyrimidinones that specifically target a polyomavirus-encoded protein, T antigen, and/or inhibit a cellular chaperone, Hsp70, that is required for virus replication.

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Brincidofovir is an oral antiviral in development for prevention of cytomegalovirus disease. Cytomegalovirus genotyping results from a phase 2 trial comparing brincidofovir to placebo for prophylaxis against cytomegalovirus infection in hematopoietic cell transplant recipients provided initial data on the clinical resistance profile for brincidofovir. In this study, no known resistance-associated mutations were detected in brincidofovir-treated subjects; identified genotypic substitutions did not confer resistance to cytomegalovirus antivirals in vitro, suggesting that these changes represent polymorphisms unrelated to brincidofovir resistance.

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Monohydroxymethyl methylenecyclopropane nucleosides (MCPNs) with ether or thioether substituents at the 6-position show promise as broad-spectrum herpes virus inhibitors. Their proposed mechanism of action involves sequential phosphorylation to a triphosphate, which can then inhibit viral DNA polymerase. The inhibition of herpes simplex virus (HSV) by these compounds is not dependent on the viral thymidine kinase (TK), which is known to phosphorylate acyclovir (ACV), a standard treatment for HSV infections.

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Article Synopsis
  • A study compared 6 months of valganciclovir therapy to the standard 6 weeks for newborns with symptomatic congenital cytomegalovirus (CMV) disease, focusing on hearing improvement and neurodevelopmental outcomes.
  • Results showed no significant difference in hearing improvement at 6 months, but at 12 and 24 months, total-ear hearing was better in the 6-month therapy group compared to the 6-week group.
  • Additionally, the longer treatment group demonstrated improved neurodevelopmental scores, although both groups experienced a similar incidence of severe neutropenia (low white blood cell count).
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Article Synopsis
  • Human herpesvirus 6 (HHV-6) usually causes mild infections but can occasionally lead to serious conditions like encephalitis, particularly in immunocompromised individuals, such as transplant recipients.
  • Currently, no approved treatments exist for HHV-6 infections, though some antiviral drugs like cidofovir and ganciclovir have shown limited success in small studies.
  • New research is focusing on the development of small molecule inhibitors of HHV-6, exploring their effectiveness and potential as broader antiviral treatments for DNA viruses.
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Article Synopsis
  • - Natural serine protease inhibitors (serpins), like antithrombin III (ATIII), activate immune responses against microbial intruders, showing promise against viral infections like HIV and HCV.
  • - ATIII demonstrated the ability to inhibit HSV infection early on and significantly reduced mortality rates in a mouse model from 90% to 40%, indicating it could effectively combat this virus.
  • - The study suggests that ATIII could be beneficial for immunocompromised patients with drug-resistant HSV-1 strains, offering potential new treatment strategies for severe viral infections.
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Article Synopsis
  • * Recent evaluations highlight the need for more effective therapies that reduce resistance and improve drug absorption, especially for high-risk patients.
  • * The review discusses existing HSV treatments and explores new therapies targeting viral components beyond DNA polymerase, particularly the helicase-primase complex.
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Unlabelled: The human cytomegalovirus (HCMV)-encoded kinase pUL97 is required for efficient viral replication. Previous studies described two isoforms of pUL97, the full-length isoform (M1) and a smaller isoform likely resulting from translation initiation at codon 74 (M74). Here, we report the detection of a third pUL97 isoform during viral infection resulting from translation initiation at codon 157 (isoform M157).

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Synopsis of recent research by authors named "Mark N Prichard"

  • - Mark N Prichard's recent research focuses primarily on the development of antiviral therapeutics targeting various DNA viruses, including cytomegalovirus (CMV), herpes simplex virus (HSV), and hepatitis B virus (HBV), aiming to overcome challenges related to drug resistance and toxicity.
  • - His investigations include analyzing mechanisms of viral transmission and diversity, as seen in studies on neonatal herpes simplex virus transmission and the mutations in viral genes that influence infection outcomes.
  • - Prichard's findings highlight the potential of novel compounds, such as NPP-669 and N-arylpyrimidinamine (NAPA), showing promise as early-stage inhibitors against CMV, as well as the need for standardized evaluation methods for antiviral activities across different laboratory settings.