| 1. |
- Groß, Rüdiger, et al.
(författare)
-
Macromolecular Viral Entry Inhibitors as Broad-Spectrum First-Line Antivirals with Activity against SARS-CoV-2
- 2022
-
Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 9:20
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of viral cell entry based on poly(styrene sulfonate) and its core–shell nanoformulations based on gold nanoparticles are investigated against a panel of viruses, including clinical isolates of SARS-CoV-2. Macromolecular inhibitors are shown to exhibit the highly sought-after broad-spectrum antiviral activity, which covers most analyzed enveloped viruses and all of the variants of concern for SARS-CoV-2 tested. The inhibitory activity is quantified in vitro in appropriate cell culture models and for respiratory viral pathogens (respiratory syncytial virus and SARS-CoV-2) in mice. Results of this study comprise a significant step along the translational path of macromolecular inhibitors of virus cell entry, specifically against enveloped respiratory viruses.
|
|
| 2. |
- Lump, Edina, et al.
(författare)
-
A molecular tweezer antagonizes seminal amyloids and HIV infection
- 2015
-
Ingår i: eLIFE. - 2050-084X. ; 4
-
Tidskriftsartikel (refereegranskat)abstract
- Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.
|
|
| 3. |
- Münch, Andreas, et al.
(författare)
-
Low-dose budesonide for maintenance of clinical remission in collagenous colitis : a randomised, placebo-controlled, 12-month trial
- 2016
-
Ingår i: Gut. - : BMJ Publishing Group. - 0017-5749 .- 1468-3288. ; 65:1, s. 47-56
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis.Design: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase.Results: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious.Conclusions: Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation.
|
|
| 4. |
- Usmani, Shariq M., et al.
(författare)
-
Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen
- 2014
-
Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 5, s. 3508-
-
Tidskriftsartikel (refereegranskat)abstract
- Naturally occurring fragments of the abundant semen proteins prostatic acid phosphatase ( PAP) and semenogelins form amyloid fibrils in vitro. These fibrils boost HIV infection and may play a key role in the spread of the AIDS pandemic. However, the presence of amyloid fibrils in semen remained to be demonstrated. Here, we use state of the art confocal and electron microscopy techniques for direct imaging of amyloid fibrils in human ejaculates. We detect amyloid aggregates in all semen samples and find that they partially consist of PAP fragments, interact with HIV particles and increase viral infectivity. Our results establish semen as a body fluid that naturally contains amyloid fibrils that are exploited by HIV to promote its sexual transmission.
|
|
| 5. |
- Weil, Tatjana, et al.
(författare)
-
Advanced Molecular Tweezers with Lipid Anchors against SARS-CoV-2 and Other Respiratory Viruses
- 2022
-
Ingår i: JACS Au. - : American Chemical Society (ACS). - 2691-3704. ; 2:9, s. 2187-2202
-
Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic caused by SARS-CoV-2 presents a global health emergency. Therapeutic options against SARS-CoV-2 are still very limited but urgently required. Molecular tweezers are supramolecular agents that destabilize the envelope of viruses resulting in a loss of viral infectivity. Here, we show that first-generation tweezers, CLR01 and CLR05, disrupt the SARS-CoV-2 envelope and abrogate viral infectivity. To increase the antiviral activity, a series of 34 advanced molecular tweezers were synthesized by insertion of aliphatic or aromatic ester groups on the phosphate moieties of the parent molecule CLR01. A structure-activity relationship study enabled the identification of tweezers with a markedly enhanced ability to destroy lipid bilayers and to suppress SARS-CoV-2 infection. Selected tweezer derivatives retain activity in airway mucus and inactivate the SARS-CoV-2 wildtype and variants of concern as well as respiratory syncytial, influenza, and measles viruses. Moreover, inhibitory activity of advanced tweezers against respiratory syncytial virus and SARS-CoV-2 was confirmed in mice. Thus, potentiated tweezers are broad-spectrum antiviral agents with great prospects for clinical development to combat highly pathogenic viruses.
|
|
| 6. |
- Westerlind, Helga, et al.
(författare)
-
Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.
- 2017
-
Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 66:3, s. 421-428
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10(-10) for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10(-11); OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.
|
|
| 7. |
- Zhang, Tankai, 1988, et al.
(författare)
-
Effects of a wave-shaped piston bowl geometry on the performance of heavy duty Diesel engines fueled with alcohols and biodiesel blends
- 2020
-
Ingår i: Renewable Energy. - : Elsevier BV. - 0960-1481 .- 1879-0682. ; 148, s. 512-522
-
Tidskriftsartikel (refereegranskat)abstract
- The effects of a new wave-shaped piston bowl design on combustion characteristics and engine out emissions were tested in a heavy duty Diesel engine fueled with conventional Diesel and fossil-free blends containing n-butanol, n-octanol, 2-ethylhexanol, hydrotreated vegetable oil, and rapeseed methyl ester. The compositions of the blends were chosen such that their cetane numbers matched that of fossil Diesel. Engine experiments were performed at four operating points from the European Stationary Cycle, with no modification of engine settings when switching between different fuels. A standard piston with omega geometry was tested using fossil Diesel and the fossil-free nBu30H (30% n-butanol and 70% hydrotreated vegetable oil by volume) blend, and the results obtained were compared to those achieved with the wave piston. In general, the fossil-free blends yielded significantly lower soot emissions than fossil Diesel but slightly higher NOx emissions. Relative to the standard piston, the wave piston accelerated the combustion of both Diesel and fossil-free blends, especially the diffusion combustion. The wave piston's positive effects on thermal efficiency and soot emissions were more pronounced for conventional Diesel fuel than for oxygenated nBu30H.
|
|
