Novel insights into the host cell glycan binding profile of human metapneumovirus.

Numerous viruses have been found to exploit glycoconjugates expressed on human cells as their initial attachment factor for viral entry and infection. The virus-cell glycointeractome, when characterized, may serve as a template for antiviral drug design. Heparan sulfate proteoglycans extensively decorate the human cell surface and were previously described as a primary receptor for human metapneumovirus (HMPV). After respiratory syncytial virus, HMPV is the second most prevalent respiratory pathogen causing respiratory tract infection in young children. To date, there is neither vaccine nor drug available to prevent or treat HMPV infection. Using a multidisciplinary approach, we report for the first time the glycointeractome of the HMPV fusion (F) protein, a viral surface glycoprotein that is essential for target-cell recognition, attachment, and entry. Our glycan microarray and surface plasmon resonance results suggest that Galß1-3/4GlcNAc moieties that may be sialylated or fucosylated are readily recognized by HMPV F. The bound motifs are highly similar to the N-linked and O-linked glycans primarily expressed on the human lung epithelium. We demonstrate that the identified glycans have the potential to compete with the cellular receptors used for HMPV entry and consequently block HMPV infection. We found that lacto-N-neotetraose demonstrated the strongest HMPV binding inhibition in a cell infection assay. Our current findings offer an encouraging and novel avenue for the design of anti-HMPV drug candidates using oligosaccharide templates.IMPORTANCEAll cells are decorated with a dense coat of sugars that makes a sugar code. Many respiratory viruses exploit this sugar code by binding to these sugars to cause infection. Human metapneumovirus is a leading cause for acute respiratory tract infections. Despite its medical importance, there is no vaccine or antiviral drug available to prevent or treat human metapneumovirus infection. This study investigates how human metapneumovirus binds to sugars in order to more efficiently infect the human host. We found that human metapneumovirus binds to a diverse range of sugars and demonstrated that these sugars can ultimately block viral infection. Understanding how viruses can take advantage of the sugar code on our cells could identify new intervention and treatment strategies to combat viral disease.

Clinical outcomes in patients with Philadelphia chromosome-positive leukemia treated with ponatinib in routine clinical practice-data from a Belgian registry.

Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016-2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.

Real-world data confirming the efficacy and safety of decitabine in acute myeloid leukaemia - results from a retrospective Belgian registry study.

Objectives: Currently, there is no standard treatment for patients with acute myeloid leukaemia (AML) ineligible for standard induction chemotherapy (IC). This study aimed to report real-world evidence data on the efficacy and safety of decitabine in this patient group.Methods: This study was a Belgian, retrospective, non-interventional, multicentre registry of patients ≥ 65 years, with newly-diagnosed de novo or secondary AML ineligible for IC. Patients were treated according to routine clinical practice. Overall survival (OS), progression-free survival (PFS) and transfusion independence for ≥8 consecutive weeks were evaluated.Results: Forty-five patients were enrolled, including 67% (n = 30) with secondary AML. Median OS and PFS were 7.3 months (95% CI: 2.2-11.1) and 4.1 months (95% CI: 2.1-7.6) respectively. A subpopulation analysis showed that patients treated with ≥4 cycles (n = 21) had significantly better outcomes compared to patients receiving <4 cycles (median OS 17.5 vs 1.6 months; median PFS 17.5 vs. 1.4 months). Twenty-five percent and 58% of patients that were respectively RBC or platelet transfusion-dependent at baseline became transfusion independent during treatment.Conclusion: This real-world data confirms that decitabine can lead to transfusion independence and longer OS in AML patients, particularly after administering ≥4 cycles, as indicated in the summary of product characteristics.

A dual drug regimen synergistically blocks human parainfluenza virus infection.

Human parainfluenza type-3 virus (hPIV-3) is one of the principal aetiological agents of acute respiratory illness in infants worldwide and also shows high disease severity in the elderly and immunocompromised, but neither therapies nor vaccines are available to treat or prevent infection, respectively. Using a multidisciplinary approach we report herein that the approved drug suramin acts as a non-competitive in vitro inhibitor of the hPIV-3 haemagglutinin-neuraminidase (HN). Furthermore, the drug inhibits viral replication in mammalian epithelial cells with an IC50 of 30 µM, when applied post-adsorption. Significantly, we show in cell-based drug-combination studies using virus infection blockade assays, that suramin acts synergistically with the anti-influenza virus drug zanamivir. Our data suggests that lower concentrations of both drugs can be used to yield high levels of inhibition. Finally, using NMR spectroscopy and in silico docking simulations we confirmed that suramin binds HN simultaneously with zanamivir. This binding event occurs most likely in the vicinity of the protein primary binding site, resulting in an enhancement of the inhibitory potential of the N-acetylneuraminic acid-based inhibitor. This study offers a potentially exciting avenue for the treatment of parainfluenza infection by a combinatorial repurposing approach of well-established approved drugs.

Study of the association of total and differential white blood cell counts with geriatric conditions, cardio-vascular diseases, seric IL-6 levels and telomere length.

BACKGROUND/OBJECTIVES: Geriatric patients are highly susceptible to infections. While reduced lymphocyte count has been associated with age, other studies found no change in WBC counts with age. Increased circulating white blood cell (WBC) count has been associated with cardiovascular (CV) diseases and frailty but there are discrepancies. Frailty, geriatric conditions, cardiovascular diseases and WBC count have also been associated with low grade inflammation. Association between geriatric conditions and WBC has been scarcely studied. The aim of the study is to assess the association between WBC and geriatric conditions, CV diseases, and seric IL-6 levels. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: We recruited 100 subjects in the general population and hospitalized for chronic medical conditions (age, 23-96years). We collected information on clinical status (medical history, comorbidities, treatments and geriatric syndromes), biological parameters (hematological tests, cytomegalovirus serology) and cytokine production (basal IL-6). Using stepwise backward multivariate analyses, we defined which set of clinical and biological variables could be predictive of increased total and differential WBC counts. RESULTS: We found that low-grade inflammation is independently associated with total WBC, monocyte and neutrophil counts, but not geriatric conditions. CV diseases were the only significant associated factor for high monocyte count. CONCLUSION: In this study, we observed that differential and total WBC counts do not seem to be associated with geriatric conditions but with CV diseases, low-grade inflammation and telomere length.

Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin-neuraminidase inhibitors.

Human parainfluenza viruses (hPIVs) cause upper and lower respiratory tract disease in children that results in a significant number of hospitalizations and impacts health systems worldwide. To date, neither antiviral drugs nor vaccines are approved for clinical use against parainfluenza virus, which reinforces the urgent need for new therapeutic discovery strategies. Here we use a multidisciplinary approach to develop potent inhibitors that target a structural feature within the hPIV type 3 haemagglutinin-neuraminidase (hPIV-3 HN). These dual-acting designer inhibitors represent the most potent designer compounds and efficiently block both hPIV cell entry and virion progeny release. We also define the binding mode of these inhibitors in the presence of whole-inactivated hPIV and recombinantly expressed hPIV-3 HN by Saturation Transfer Difference NMR spectroscopy. Collectively, our study provides an antiviral preclinical candidate and a new direction towards the discovery of potential anti-parainfluenza drugs.