scholarly journals Drug discovery in leishmaniasis using protein lipidation as a target

2021 ◽  
Author(s):  
James A. Brannigan ◽  
Anthony J. Wilkinson
Keyword(s):  
High Throughput Screening ◽  
Drug Target ◽  
Leishmania Donovani ◽  
Covalent Modification ◽  
High Morbidity ◽  
Lead Compounds ◽  
Frontline Treatment ◽  
The Stability ◽  
Substrate Proteins

AbstractThe leishmaniases are infectious diseases caused by a number of species of obligate intracellular protozoa of the genus Leishmania with disease manifesting as cutaneous, mucocutaneous and visceral forms. Despite being endemic in more than 80 countries and its being the cause of high morbidity and mortality, leishmaniasis remains a neglected tropical disease. Chemotherapy is the frontline treatment, but drugs in current use suffer from toxic side effects, difficulties in administration and extended treatment times — moreover, resistance is emerging. New anti-leishmanial drugs are a recognised international priority. Here, we review investigations into N-myristoyltransferase (NMT) as a potential drug target. NMT catalyses the co-translational transfer of a C14 fatty acid from myristoyl-CoA onto the N-terminal glycine residue of a significant subset of proteins in eukaryotic cells. This covalent modification influences the stability and interactions of substrate proteins with lipids and partner proteins. Structure-guided development of new lead compounds emerging from high-throughput screening campaigns targeting Leishmania donovani NMT has led to the discovery of potent inhibitors which have been used to gain insights into the role of protein myristoylation in these parasites and to validate NMT as a drug target.

scholarly journals Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay

2021 ◽  
Author(s):  
Zilei Xia ◽  
Michael Sacco ◽  
Chunlong Ma ◽  
Julia Townsend ◽  
Naoya Kitamura ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Drug Target ◽  
Antiviral Drug ◽  
Single Digit ◽  
Lead Compounds ◽  
High Profile ◽  
Ic50 Values ◽  
Host Innate Immune Response ◽  
Inhibition Potency

The papain-like protease (PLpro) of SARS-CoV-2 is a validated antiviral drug target. PLpro is involved in the cleavage of viral polyproteins and antagonizing host innate immune response through its deubiquitinating and deISG15ylating activities, rendering it a high profile antiviral drug target. Through a FRET-based high-throughput screening, several hits were identified as PLpro inhibitors with IC50 values at the single-digit micromolar range. Subsequent lead optimization led to potent inhibitors with IC50 values ranging from 0.56 to 0.90 micromolar. To help prioritize lead compounds for the cellular antiviral assay against SARS-CoV-2, we developed the cell-based FlipGFP assay that is suitable for quantifying the intracellular enzymatic inhibition potency of PLpro inhibitors in the BSL-2 setting. Two compounds selected from the FlipGFP-PLpro assay, Jun9-53-2 and Jun9-72-2, inhibited SARS-CoV-2 replication in Caco-2 hACE2 cells with EC50 values of 8.89 and 8.32 micromolar, respectively, which were 3-fold more potent than GRL0617 (EC50 = 25.1 micromolar). The X-ray crystal structures of PLpro in complex with GRL0617 showed that binding of GRL0617 to SARS-CoV-2 induced a conformational change in the BL2 loop to the more closed conformation. Overall, the PLpro inhibitors identified in this study represent promising starting points for further development as SARS-CoV-2 antivirals, and FlipGFP-PLpro assay might be a suitable surrogate for screening PLpro inhibitors in the BSL-2 setting.

New Aspects of Monoamine Oxidase B Inhibitors: The Key Role of Halogens to Open the Golden Door

2020 ◽  
Vol 28 (2) ◽  
pp. 266-283 ◽  
Author(s):  
Bijo Mathew ◽  
Simone Carradori ◽  
Paolo Guglielmi ◽  
Md. Sahab Uddin ◽  
Hoon Kim
Keyword(s):  
Monoamine Oxidase ◽  
Drug Target ◽  
Halogen Bonds ◽  
Target Interaction ◽  
Lead Compounds ◽  
Structure Activity ◽  
Pharmacodynamic Profile ◽  
The Impact ◽  
Important Enzyme

A large plethora of drugs and promising lead compounds contain halogens in their structures. The introduction of such moieties strongly modulates their physical-chemical features as well as pharmacokinetic and pharmacodynamic profile. The most important outcome was shown to be the ability of these halogens to favourably influence the drug-target interaction and energetic stability within the active site by the establishment of halogen bonds. This review attempted to demonstrate the key role exerted by these versatile moieties when correctly located in an organic scaffold to display Monoamine Oxidase (MAO) inhibition and selectivity towards the B isoform of this important enzyme. Human MAOs are well-recognized as therapeutic targets for mood disorders and neurodegenerative diseases and medicinal chemists were prompted to discover the structural requirements crucial to discriminate the slight differences between the active sits of the two isoforms (MAO-A and MAOB). The analysis of the structure-activity relationships of the most important scaffolds (hydrazothiazoles, coumarins, chromones, chalcones, pyrazolines) and the impact of halogen (F, Cl, Br and I) insertion on this biological activity and isozyme selectivity have been reported being a source of inspiration for the medicinal chemists.

The RNA Binding Protein HuR: a Promising Drug Target for Anticancer Therapy

2019 ◽  
Vol 19 (5) ◽  
pp. 382-399 ◽  
Author(s):  
Mingxia Wu ◽  
Christy W.S. Tong ◽  
Wei Yan ◽  
Kenneth K.W. To ◽  
William C.S. Cho
Keyword(s):  
Targeted Delivery ◽  
High Throughput Screening ◽  
Drug Target ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Target Mrnas ◽  
Recognition Motifs ◽  
The Stability ◽  
And Function

The stability of mRNA is one of the key factors governing the regulation of eukaryotic gene expression and function. Human antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. While HuR is normally localized within the nucleus, it has been shown that HuR binds mRNAs in the nucleus and then escorts the mRNAs to the cytoplasm where HuR protects them from degradation. It contains several RNA recognition motifs, which specifically bind to adenylate and uridylate-rich regions within the 3’-untranslated region of the target mRNA to mediate its effect. Many of the HuR target mRNAs encode proteins important for cell growth, tumorigenesis, angiogenesis, tumor inflammation, invasion and metastasis. HuR overexpression is known to correlate well with high-grade malignancy and poor prognosis in many tumor types. Thus, HuR has emerged as an attractive drug target for cancer therapy. Novel small molecule HuR inhibitors have been identified by high throughput screening and new formulations for targeted delivery of HuR siRNA to tumor cells have been developed with promising anticancer activity. This review summarizes the significant role of HuR in cancer development, progression, and poor treatment response. We will discuss the potential and challenges of targeting HuR therapeutically.

scholarly journals Description of a Novel Fameshifting Site in the 5'UTR of SARS-CoV-2 as a Potential Drug Target

2021 ◽  
Author(s):  
Emilio Garcia-Moran ◽  
Marta Hernandez ◽  
David Abad ◽  
Jose Maria Eiros
Keyword(s):  
Secondary Structure ◽  
Drug Target ◽  
3D Structure ◽  
Oral Drugs ◽  
Bioinformatic Tools ◽  
Lead Compounds ◽  
The World ◽  
Positive Sense ◽  
Potential Regulatory Role

Abstract SARS-CoV-2 is an enveloped positive-sense single-stranded RNA coronavirus that causes COVID-19 whose present outbreak has cost a high number of casualties throughout the world. The aim of this work was to scan the SARS-CoV-2 genome in search for new therapeutic targets. We found a sequence in the 5'UTR (NC 045512:74-130), consisting of a typical heptamer next to a structured region that may cause frameshifting. The potential biological value of this region is shown by its similarity with other coronaviruses related with SARS-CoV and its sequence conservation within isolates from SARS-CoV-2. We have predicted the secondary structure of the region by means of different bioinformatic tools. We have chosen a probable secondary structure to proceed with a 3D reconstruction of the structured segment. We carried out virtual docking on the 3D structure to look for a binding site and then for drug ligands from a database of lead compounds. Several molecules that would probably administered as oral drugs show promising binding affinity within the structured region and so it would be possible interfere the potential regulatory role of our sequence of interest.

Characterization of phosphate transporter(s) and understanding their role in Leishmania donovani parasite

2018 ◽  
Vol 63 (1) ◽  
pp. 75-88 ◽  
Author(s):  
K.J. Sindhu ◽  
Amit Kumar Kureel ◽  
Sheetal Saini ◽  
Smita Kumari ◽  
Pankaj Verma ◽  
...  
Keyword(s):  
Inorganic Phosphate ◽  
Drug Target ◽  
Leishmania Donovani ◽  
Physiological Role ◽  
Parasite Life Cycle ◽  
Phosphate Transporters ◽  
Promastigote Form ◽  
Specific Inhibitors

Abstract Inorganic phosphate (Pi) is shown to be involved in excretion of methylglyoxal (MG) in the promastigote form of Leishmania donovani parasite. Absence of Pi leads to its accumulation inside the parasite. Accumulation of MG is toxic to the parasite and utilizes glyoxylase as well as excretory pathways for its detoxification. In addition, Pi is also reported to regulate activities of ectoenzymes and energy metabolism (glucose to pyruvate) etc. Thus, it is known to cumulatively affect the growth of Leishmania parasite. Hence the transporters, which allow the movement of Pi across the membrane, can prove to be a crucial drug target. Therefore, we characterized two phosphate transporters in Leishmania (i) H+ dependent myo-inositol transporter (LdPHO84), and (ii) Na+ dependent transporter (LdPHO89), based on similar studies done previously on other lower organisms and trypanosomatids. We tried to understand the secondary structure of these two proteins and confirm modulation in their expression with the change in Pi concentration outside. Moreover, their modes of action were also measured in the presence of specific inhibitors (LiF, CCCP). Further analysis on the physiological role of these transporters in various stages of the parasite life cycle needs to be entrenched.

A Statistical Study of Process Variables to Optimize a High Speed Curtain Coater: Part I

TAPPI Journal ◽  
2009 ◽  
Vol 8 (1) ◽  
pp. 20-26 ◽  
Author(s):  
PEEYUSH TRIPATHI ◽  
MARGARET JOYCE ◽  
PAUL D. FLEMING ◽  
MASAHIRO SUGIHARA
Keyword(s):  
Boundary Layer ◽  
Experimental Design ◽  
High Speed ◽  
Statistical Study ◽  
Process Variables ◽  
High Speeds ◽  
The Stability ◽  
Air Removal ◽  
Removal System

Using an experimental design approach, researchers altered process parameters and material prop-erties to stabilize the curtain of a pilot curtain coater at high speeds. Part I of this paper identifies the four significant variables that influence curtain stability. The boundary layer air removal system was critical to the stability of the curtain and base sheet roughness was found to be very important. A shear thinning coating rheology and higher curtain heights improved the curtain stability at high speeds. The sizing of the base sheet affected coverage and cur-tain stability because of its effect on base sheet wettability. The role of surfactant was inconclusive. Part II of this paper will report on further optimization of curtain stability with these four variables using a D-optimal partial-facto-rial design.

The Role of Hydrophobicity in the Stability and pH-Switchability of (RXDX)4 and Coumarin-RXDX Conjugate β-Sheets

2020 ◽  
Author(s):  
Ryan Weber ◽  
Martin McCullagh
Keyword(s):  
Biological Imaging ◽  
Ph Sensing ◽  
Hydrophobic Residue ◽  
Ideal Candidate ◽  
Self Assembling ◽  
Sensing Applications ◽  
Β Sheets ◽  
The Stability ◽  
Dynamics Simulations

<p>pH-switchable, self-assembling materials are of interest in biological imaging and sensing applications. Here we propose that combining the pH-switchability of RXDX (X=Ala, Val, Leu, Ile, Phe) peptides and the optical properties of coumarin creates an ideal candidate for these materials. This suggestion is tested with a thorough set of all-atom molecular dynamics simulations. We first investigate the dependence of pH-switchabiliy on the identity of the hydrophobic residue, X, in the bare (RXDX)<sub>4</sub> systems. Increasing the hydrophobicity stabilizes the fiber which, in turn, reduces the pH-switchabilty of the system. This behavior is found to be somewhat transferable to systems in which a single hydrophobic residue is replaced with a coumarin containing amino acid. In this case, conjugates with X=Ala are found to be unstable and both pHs while conjugates with X=Val, Leu, Ile and Phe are found to form stable β-sheets at least at neutral pH. The (RFDF)<sub>4</sub>-coumarin conjugate is found to have the largest relative entropy value of 0.884 +/- 0.001 between neutral and acidic coumarin ordering distributions. Thus, we posit that coumarin-(RFDF)<sub>4</sub> containing peptide sequences are ideal candidates for pH-sensing bioelectronic materials.</p>

Metal-Metal Cooperative Bond Activation by Heterobimetallic Alkyl, Aryl, and Acetylide PtII/CuI Complexes

2020 ◽  
Author(s):  
Shubham Deolka ◽  
Orestes Rivada Wheelaghan ◽  
Sandra Aristizábal ◽  
Robert Fayzullin ◽  
Shrinwantu Pal ◽  
...  
Keyword(s):  
Alkyl Group ◽  
Bond Activation ◽  
Bond Cleavage ◽  
Terminal Alkyne ◽  
Alkyl Aryl ◽  
Metal Metal ◽  
The Stability ◽  
Selective Formation ◽  
Organoplatinum Compounds

We report selective formation of heterobimetallic PtII/CuI complexes that demonstrate how facile bond activation processes can be achieved by altering reactivity of common organoplatinum compounds through their interaction with another metal center. The interaction of the Cu center with Pt center and with a Pt-bound alkyl group increases the stability of PtMe2 towards undesired rollover cyclometalation. The presence of the CuI center also enables facile transmetalation from electron-deficient tetraarylborate [B(ArF)4]- anion and mild C-H bond cleavage of a terminal alkyne, which was not observed in the absence of an electrophilic Cu center. The DFT study indicates that the role of Cu center acts as a binding site for alkyne substrate, while activating its terminal C-H bond.

LANDSLIDE RISK MANAGEMENT IN THE COASTAL ZONE OF THE KUIBYSHEV RESERVOIR DUE THE DESIGN OF HIGH-SPEED LINE "MOSCOW-KAZAN"

2017 ◽  
Author(s):  
Nikolai Petrov ◽  
Nikolai Petrov ◽  
Inna Nikonorova ◽  
Inna Nikonorova ◽  
Vladimir Mashin ◽  
...  
Keyword(s):  
High Speed ◽  
Computational Models ◽  
Stable State ◽  
Landslide Risk ◽  
Kuibyshev Reservoir ◽  
Stepped Surface ◽  
The Stability ◽  
Landslide Slope ◽  
The Village

High-speed railway "Moscow-Kazan" by the draft crosses the Volga (Kuibyshev reservoir) in Chuvashia region 500 m below the village of New Kushnikovo. The crossing plot is a right-bank landslide slope with a stepped surface. Its height is 80 m; the slope steepness -15-16o. The authors should assess the risk of landslides and recommend anti-landslide measures to ensure the safety of the future bridge. For this landslide factors have been analyzed, slope stability assessment has been performed and recommendations have been suggested. The role of the following factors have been analyzed: 1) hydrologic - erosion and abrasion reservoir and runoff role; 2) lithologyc (the presence of Urzhum and Northern Dvina horizons of plastically deformable rocks, displacement areas); 3) hydrogeological (the role of perched, ground and interstratal water); 4) geomorphological (presence of the elemental composition of sliding systems and their structure in the relief); 5) exogeodynamic (cycles and stages of landslide systems development, mechanisms and relationship between landslide tiers of different generations and blocks contained in tiers). As a result 6-7 computational models at each of the three engineering-geological sections were made. The stability was evaluated by the method “of the leaning slope”. It is proved that the slope is in a very stable state and requires the following measures: 1) unloading (truncation) of active heads blocks of landslide tiers) and the edge of the plateau, 2) regulation of the surface and groundwater flow, 3) concrete dam, if necessary.

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