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The search for new therapies for human cytomegalovirus infections.

ABSTRACT: Ganciclovir (GCV), the therapy of choice for human cytomegalovirus (CMV) infections and foscarnet, a drug used to treat GCV-resistant CMV infections was approved more than twenty years ago. Although cidofovir and a prodrug of GCV have since been added to the armamentarium, a highly effective drug without significant toxicities has yet to be approved. Such a therapeutic agent is required for treatment of immunocompromised hosts and infants, which bear the greatest burden of disease. The modest antiviral activity of existing drugs is insufficient to completely suppress viral replication, which results in the selection of drug-resistant variants that remain pathogenic, continue to replicate, and contribute to disease. Sustained efforts, largely in the biotech industry and academia, have identified highly active lead compounds that have progressed into clinical studies with varying levels of success. A few of these compounds inhibit new molecular targets, remain effective against isolates that have developed resistance to existing therapies, and promise to augment existing therapies. Some of the more promising drugs will be discussed with an emphasis on those progressing to clinical studies. Their antiviral activity both in vitro and in vivo, spectrum of antiviral activity, and mechanism of action will be reviewed to provide an update on the progress of potential new therapies for CMV infections.

SUBMITTER: Prichard MN

PROVIDER: S-EPMC3068221 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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The search for new therapies for human cytomegalovirus infections.

Prichard Mark N MN Kern Earl R ER

Virus research 20101121 2

Ganciclovir (GCV), the therapy of choice for human cytomegalovirus (CMV) infections and foscarnet, a drug used to treat GCV-resistant CMV infections was approved more than twenty years ago. Although cidofovir and a prodrug of GCV have since been added to the armamentarium, a highly effective drug without significant toxicities has yet to be approved. Such a therapeutic agent is required for treatment of immunocompromised hosts and infants, which bear the greatest burden of disease. The modest an ...[more]

PMID: 21095209

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Project description:Background: Human cytomegalovirus (HCMV) infects ~50% of adults in the United States. HCMV infections may cause vascular inflammation leading to cardiovascular disease, but the existing evidence is inconsistent. Objective: We investigated demographic predictors of HCMV infection and explored associations between HCMV infection status, the intensity of anti-HCMV Immunoglobulin G (IgG) antibody response, and biomarkers of inflammation and endothelial function which are known predictors of cardiovascular disease. Methods: We conducted a cross-sectional study of 694 adults residing in the Raleigh-Durham-Chapel Hill, NC metropolitan area. Serum samples were tested for IgG antibody response to HCMV, and for biomarkers of vascular injury including soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), C-reactive protein (CRP), and serum amyloid A (SAA). Associations between HCMV and biomarker levels were analyzed using two approaches with HCMV serostatus modeled as a binary variable and as an ordinal variable with five categories comprised of seronegative individuals and quartiles of anti-HCMV antibody responses in seropositive individuals. Results: HCMV seroprevalence in the study population was 56%. Increased body mass index, increased age, female gender, racial/ethnic minority status, and current smoking were significantly associated with HCMV seropositivity in a multivariate regression analysis. HCMV seropositivity was also associated with 9% (95% confidence interval 4-15%) and 20% (0.3-44%) increases in median levels of sICAM-1 and CRP, respectively, after adjusting for covariates. The association between HCMV seropositivity and median levels of sVCAM-1 and SAA were positive but not statistically significant. Significant positive associations were observed between the intensity of anti-HCMV IgG responses and levels of sICAM-1 and sVCAM-1 (p-values 0.0008 and 0.04 for linear trend, respectively). To our knowledge, this is the first epidemiological study to show a relationship between anti-HCMV IgG responses and vascular injury biomarkers sICAM-1 and sVCAM-1 in the general population. Conclusion: HCMV infections are associated with vascular injury and inflammation biomarkers in adult residents of North Carolina.

Project description:BackgroundThis systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction.MethodsThe databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework.ResultsForty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability.DiscussionMost of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis.ConclusionA panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.

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The search for new therapies for human cytomegalovirus infections.

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The search for new therapies for human cytomegalovirus infections.

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