Search results for "protease inhibitors"
showing 10 items of 98 documents
Bioassays to monitor taspase1 function for the identification of pharmacogenetic inhibitors
2011
Background Threonine Aspartase 1 (Taspase1) mediates cleavage of the mixed lineage leukemia (MLL) protein and leukemia provoking MLL-fusions. In contrast to other proteases, the understanding of Taspase1's (patho)biological relevance and function is limited, since neither small molecule inhibitors nor cell based functional assays for Taspase1 are currently available. Methodology/Findings Efficient cell-based assays to probe Taspase1 function in vivo are presented here. These are composed of glutathione S-transferase, autofluorescent protein variants, Taspase1 cleavage sites and rational combinations of nuclear import and export signals. The biosensors localize predominantly to the cytoplasm…
Future Directions in the Pharmacologic Therapy of Chronic Obstructive Pulmonary Disease
2005
Current therapy for chronic obstructive pulmonary disease (COPD) fails to alter its relentless progression. This remains a significant challenge and unmet need. A recent advance is the demonstration that treatment with a fixed dose of an inhaled corticosteroid and a long-acting beta2-agonist in COPD improves lung function and quality of life, and reduces exacerbation more effectively than either drug alone. Other improvements include the introduction of tiotropium, a once-daily anticholinergic. In advanced clinical development are other once-daily bronchodilators and combinations of anticholinergic drugs and beta2-agonists. Increased understanding of the pathogenesis of COPD has led to nove…
In silico molecular investigations of pyridine N-Oxide compounds as potential inhibitors of SARS-CoV-2: 3D QSAR, molecular docking modeling, and ADME…
2020
The new coronavirus SARS-CoV-2 virus is causing a severe pneumonia in human, provoking the serious outbreak epidemic CoV-2. Since its appearance in Wuhan, China on December 2019, CoV-2 becomes the biggest challenge the world is facing today, including the discovery of antiviral drug for SARS-CoV-2. In this study, the potential inhibitory of a class of human SARS inhibitors, namely pyridine N-oxide derivatives, against CoV-2 was addressed by quantitative structure-activity relationship 3 D-QSAR. The reliable CoMSIA developed model of 110 pyridine N-oxide based-antiviral compounds, showed Q
Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease.
2021
We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against the SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions P3 and P4 could be susceptible to improvement in order to get a larger binding strength. QM/MM simulations unveil the reaction mechanism for covalent inhibition, showing that the nitrile warhead facilitates the recruitment of a water molecule for the proton transfer step.
Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives
2022
The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine145 of SARS-CoV-2 MPRO with selective antiviral drugs will arrest the replication process of the virus without affecting human catalytic pathways. In this Perspective, we analyzed the in silico, in vitro, and in vivo data of the most representative examples of covalent SARS-CoV-2 MPRO inhibitors reported in the literature to date. In particular, the studied molecules were classified into eight different categories according to their reactive electrophilic warheads, highlighting the differences between their reversible/irreversible mech…
A Multivariate Analysis of HIV-1 Protease Inhibitors and Resistance Induced by Mutation
2005
This paper describes the use of the multivariate statistical procedure principal component analysis as a tool to explore the inhibitory activity of classes of protease inhibitors (PIs) against HIV-1 viruses (wild type and more-frequent single mutants, V82A, V82F, and I84V) and against protease enzymes. The analysis of correlations between biological activity and molecular descriptors or similarity indexes allowed a reliable classification of the 51 derivatives considered in this study. The best results were obtained in the case of the I84V mutant for which a high number of predictions was achieved. On this basis, this statistical approach is proposed as a reliable method for the prediction …
Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold-Hopping Approach.
2020
Abstract Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug‐discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. …
Consistency of Carbopol 971-P NF gels and influence of soluble and cross-linked PVP.
2002
A study is made of the polymerization process of polyacrylic acid, commercially known as Carbopol® 971 NF, assessing its consistency as a function of the degree of neutralization at pH values from 3 to 12, approximately. Percentage concentrations ranging from 0.1 to 1.4% (w/w) were studied. The gels obtained were non-Newtonian, and pseudoplastic. As concentration and pH rise, the consistency of the gels increase to a maximum, which appears between pH 6 and 8, allowing their use as vehicles in bioadhesive formulations for mucosal application. Over the increasing viscosity interval, functions were obtained to indicate the consistency of the gel as a function of pH and concentration. Since the…
Proteomic analysis of the acid-soluble nacre matrix of the bivalve Unio pictorum: detection of novel carbonic anhydrase and putative protease inhibit…
2010
10 pages; International audience; The matrix extracted from mollusc shell nacre is a mixture of proteins and glycoproteins that is thought to play a major role in controlling biomineral synthesis and in increasing its mechanical properties. We investigated the nacreous shell of the freshwater mussel Unio pictorum, to which we applied a proteomics approach adapted to mollusc shell proteins. On one hand, the acid-soluble nacre matrix was fractionated by SDS-PAGE and the five main protein bands (P95, P50, P29, P16, and P12) were digested with trypsin and analyzed by nanoLC-MS/MS followed by de novo sequencing. On the other hand, the acid-soluble nacre matrix was analyzed in a similar manner, w…
Induction of apoptosis in human osteosarcoma Saos-2 cells by the proteasome inhibitor MG132 and the protective effect of pRb
2003
Induction of apoptosis in human osteosarcoma Saos-2 cells by the proteasome inhibitor MG132 and the protective effect of pRb