Search results for "protease inhibitors"
showing 10 items of 98 documents
Identification of Plakortide E from the Caribbean Sponge Plakortis halichondroides as a Trypanocidal Protease Inhibitor using Bioactivity-Guided Frac…
2014
In this paper, we report new protease inhibitory activity of plakortide E towards cathepsins and cathepsin-like parasitic proteases. We further report on its anti-parasitic activity against Trypanosoma brucei with an IC50 value of 5 mu M and without cytotoxic effects against J774.1 macrophages at 100 mu M concentration. Plakortide E was isolated from the sponge Plakortis halichondroides using enzyme assay-guided fractionation and identified by NMR spectroscopy and mass spectrometry. Furthermore, enzyme kinetic studies confirmed plakortide E as a non-competitive, slowly-binding, reversible inhibitor of rhodesain.
Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis
1998
Asthma and chronic bronchitis are inflammatory diseases with extracellular matrix (ECM) remodeling and collagen deposition. Collagen homeostasis is controlled by metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). We evaluated MMP and TIMP balance in induced sputum of 10 control, 31 untreated asthmatic, and 16 chronic bronchitic subjects. We first performed zymographic analysis to identify the profile of MMPs. Zymography revealed a similar MMPs profile in all populations studied and that MMP-9 was the major enzyme released. We then measured, using enzyme immunoassay, the concentrations of MMP-9 and of its inhibitor TIMP-1 and evaluated whether airflow limitation m…
Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach
2022
Vitamin D’s role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D2), 7-dehydrocholesterol (provitamin-D3), 22,23-dihydroergocalciferol (provitamin-D4), cholecalciferol (vitamin-D3), and ergocalciferol (vitamin D2) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unr…
Long-term CD4+ T-cell count evolution after switching from regimens including HIV nucleoside reverse transcriptase inhibitors (NRTI) plus protease in…
2011
Abstract Background Data regarding CD4+ recovery after switching from protease inhibitor (PI)-based regimens to regimens not containing PI are scarce. Methods Subjects with virological success on first-PI-regimens who switched to NNRTI therapy (NNRTI group) or to nucleoside reverse transcriptase (NRTI)-only (NRTI group) were studied. The effect of the switch on the ongoing CD4+ trend was assessed by two-phase linear regression (TPLR), allowing us to evaluate whether a change in the CD4+ trend (hinge) occurred and the time of its occurrence. Furthermore, we described the evolution of the frequencies in CD4-count classes across four relevant time-points (baseline, before and immediately after…
A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases
2016
Abstract N′-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., K i = 65 nM of 1u for Hs APN). Two structures of an M1 representative (APN from Neisser…
Functional and Pharmacological Analyses of the Role of Penicillium digitatum Proteases on Virulence
2019
© The Author(s).
Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
2019
The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modificati…
A phosphonamidate containing aromatic N-terminal amino group as inhibitor of leucine aminopeptidase-design, synthesis and stability.
2006
Fully deprotected phosphonamidate dipeptides, predicted as effective inhibitors of cytosolic leucine aminopeptidase, showed unexpected instability in water solution at pH below 12. Their hydrolysis rate was strictly correlated with basicity of the N-terminal amino group. To improve this feature a phosphonamidate analogue containing less basic, aromatic 2-aminophenylphosphonate residue in P1 position of the inhibitor was designed. The target compound was synthesised starting from diethyl 2-nitrophosphonate in several step procedure. The decrease in basicity of the terminal amino moiety of the modified analogue in fact resulted in satisfactory improvement of hydrolytic stability of the P–N bo…
The future: critical knowledge about anti-itch therapy.
2005
: Itch is an extremely frequent and enervating symptom of many diseases. Current anti-itch therapy, which is based almost exclusively on an “immunocentric” viewpoint, is often unsatisfactory. Recent studies show that this symptom is in fact the result of a complex interplay among skin, nervous system, endocrine system, and immune system. This explains the frequent failure of therapeutic strategies focused only on a single factor and suggests the usefulness of a polypharmacologic symptomatic treatment, designed on a case-by-case basis as a result of a multidisciplinary approach. We discuss the perspectives of anti-itch therapy in light of the new pathogenetic and pharmacologic acquisitions.
Twenty Years of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Time to Reevaluate their Toxicity
2011
Twenty years of effective clinical application have consolidated non-nucleoside reverse transcriptase inhibitors (NNRTI) as essential components of the Highly Active Antiretroviral Therapy (HAART) employed in the treatment of Human Immunodeficiency Virus (HIV). However, as the disease has come under control, there has been growing emphasis on the long-term adverse effects induced by this chronic pharmacological therapy. Although traditionally considered to be safe and well-tolerated drugs, there is mounting evidence that associates NNRTI with the onset of cutaneous reactions, neuropsychiatric symptoms, hepatotoxicity, metabolic disturbances and gastrointestinal toxicity. Though the clinical…