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Cold Spring Harbor Perspectives in... Jan 2022The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic)... (Review)
Review
The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.
Topics: Antibodies, Monoclonal; Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Zanamivir
PubMed: 32152244
DOI: 10.1101/cshperspect.a038455 -
CMAJ : Canadian Medical Association... May 2021
Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Humans; Risk Factors
PubMed: 34001550
DOI: 10.1503/cmaj.202308 -
Molecular Cancer Therapeutics Dec 2021The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene...
The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models , with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity-driven tumors.
Topics: Animals; Disease Models, Animal; Enzyme Inhibitors; Humans; Lung Neoplasms; Mice; Protein-Arginine N-Methyltransferases; Pyrimidines; Pyrroles
PubMed: 34583982
DOI: 10.1158/1535-7163.MCT-21-0367 -
International Journal of Nanomedicine 2021Nanozyme is a type of nanomaterial with intrinsic enzyme-like activity. Following the discovery of nanozymes in 2007, nanozyme technology has become an emerging field... (Review)
Review
Nanozyme is a type of nanomaterial with intrinsic enzyme-like activity. Following the discovery of nanozymes in 2007, nanozyme technology has become an emerging field bridging nanotechnology and biology, attracting research from multi-disciplinary areas focused on the design and synthesis of catalytically active nanozymes. However, various types of enzymes can be mimicked by nanomaterials, and our current understanding of nanozymes as enzyme inhibitors is limited. Here, we provide a brief overview of the utility of nanozymes as inhibitors of enzymes, such as R-chymotrypsin (ChT), β-galactosidase (β-Gal), β-lactamase, and mitochondrial F0F1-ATPase, and the mechanisms underlying inhibitory activity. The advantages, challenges and future research directions of nanozymes as enzyme inhibitors for biomedical research are further discussed.
Topics: Animals; Biomimetics; Catalysis; Enzyme Inhibitors; Enzymes; Humans; Nanostructures; Nanotechnology
PubMed: 33603373
DOI: 10.2147/IJN.S294871 -
Advances in Experimental Medicine and... 2022DNA methylation is involved in numerous biological processes and is deregulated in human diseases. The modulation of the activity of the enzymes and proteins in charge... (Review)
Review
DNA methylation is involved in numerous biological processes and is deregulated in human diseases. The modulation of the activity of the enzymes and proteins in charge of DNA methylation, for example, DNA methyltransferases (DNMTs), can represent a powerful strategy to alter DNA methylation patterns and restore biological processes that are aberrant in diseases. In this chapter, we present examples of inhibitors of DNMTs (DNMTi). We review their fields of application either as therapeutic molecules, for example, in cancers, cardiovascular, neurological, and infectious diseases or as bioengineering tools. Finally, novel strategies to target DNA methylation and overcome the limits of single DNMT inhibitors will be described. These strategies consist in either targeting the methyl group reader proteins rather than targeting directly DNMTs or to combine within the same molecule a DNMT inhibitor with an additional active moiety, e.g., HDAC inhibitor, to improve efficacy and lower secondary effect of such drug.
Topics: Humans; DNA Methylation; Neoplasms; DNA Modification Methylases; Enzyme Inhibitors; Histone Deacetylase Inhibitors; DNA (Cytosine-5-)-Methyltransferases
PubMed: 36350520
DOI: 10.1007/978-3-031-11454-0_17 -
Journal of Medicinal Chemistry Mar 2024Continually repeating outbreaks of pathogenic viruses necessitate the construction of effective antiviral strategies. Therefore, the development of new specific... (Review)
Review
Continually repeating outbreaks of pathogenic viruses necessitate the construction of effective antiviral strategies. Therefore, the development of new specific antiviral drugs in a well-established and efficient manner is crucial. Taking into account the strong ability of viruses to change, therapies with diversified molecular targets must be sought. In addition to the widely explored viral enzyme inhibitor approach, inhibition of protein-protein interactions is a very valuable strategy. In this Perspective, protein-protein interaction inhibitors targeting HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya viruses are reviewed and discussed. Antibodies, peptides/peptidomimetics, and small molecules constitute three classes of compounds that have been explored, and each of them has some advantages and disadvantages for drug development.
Topics: Humans; Antiviral Agents; Viruses; Enzyme Inhibitors; Chikungunya virus; Hemorrhagic Fever, Ebola
PubMed: 38394369
DOI: 10.1021/acs.jmedchem.3c01543 -
Cancer Cell Jul 2019Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in...
Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.
Topics: Alternative Splicing; Antineoplastic Agents; Biomarkers; Cell Line, Tumor; Drug Synergism; Enzyme Inhibitors; Humans; Methylation; Models, Molecular; Molecular Conformation; Molecular Structure; Protein Binding; Protein-Arginine N-Methyltransferases; Purine-Nucleoside Phosphorylase; Substrate Specificity
PubMed: 31257072
DOI: 10.1016/j.ccell.2019.05.014 -
Journal of Medicinal Chemistry Jul 2020Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies...
Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRAS that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate as a potent, selective covalent inhibitor of KRAS is described.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Mice; Models, Molecular; Mutation; Proto-Oncogene Proteins p21(ras); Xenograft Model Antitumor Assays
PubMed: 32250617
DOI: 10.1021/acs.jmedchem.9b02052 -
Circulation Aug 2022The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration.
METHODS
Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress.
RESULTS
Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m lower GFR compared with placebo-ramipril treatment (=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure-lowering effects (clinic systolic blood pressure lower by 4 mm Hg [=0.0112]; diastolic blood pressure lower by 3 mm Hg [=0.0032]) in conjunction with a 94.5 dynes × sex/cm lower total peripheral resistance (=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin.
CONCLUSIONS
Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT02632747.
Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Glomerular Filtration Rate; Glucose; Humans; Ramipril; Sodium; Sodium-Glucose Transporter 2
PubMed: 35862082
DOI: 10.1161/CIRCULATIONAHA.122.059150 -
SLAS Discovery : Advancing Life... Feb 2021Enzymes represent a significant proportion of the druggable genome and constitute a rich source of drug targets. Delivery of a successful program for developing a...
Enzymes represent a significant proportion of the druggable genome and constitute a rich source of drug targets. Delivery of a successful program for developing a modulator of enzyme activity requires an understanding of the enzyme's mechanism and the mode of interaction of compounds. This allows an understanding of how physiological conditions in disease-relevant cells will affect inhibitor potency. As a result, there is increasing interest in evaluating hit compounds from high-throughput screens to determine their mode of interaction with the target. This work revisits the common inhibition modalities and illustrates the impact of substrate concentration relative to K upon the pattern of changes in IC that are expected for increasing substrate concentration. It proposes a new, high-throughput approach for assessing mode of inhibition, incorporating analyses based on a minimal descriptive model, to deliver a workflow that allows rapid and earlier compound classification immediately after high-throughput screening.
Topics: Drug Discovery; Enzyme Activation; Enzyme Inhibitors; Enzymes; High-Throughput Screening Assays; Humans; Substrate Specificity; Workflow
PubMed: 33482076
DOI: 10.1177/2472555220983809