Mammalian carboxylesterase (CES) releases GPI-anchored proteins from the cell surface upon lipid raft fluidization

Abstract Mammalian carboxylesterase (CES) is well known as a biotransformation enzyme for prodrugs and xenobiotics. Here, we purified CES as a GPI-anchored protein (GPI-AP)-releasing factor (GPIase) that releases such protein from the cell surface. All five isoforms of CES showed this activity to various degrees. When the serine residue of the catalytic triad for esterase was replaced by alanine, esterase activity was completely disrupted, while full GPIase activity remained, suggesting that these two activities are exhibited via different mechanisms. CES6, a new class of mammalian CES, exhibited the highest GPIase activity and released specific GPI-APs from the cell surface after lipid raft fluidization. The released product contained a GPI component, indicating that GPI-AP was released by cleavage in GPI. These results revealed for the first time that CES recognizes and catalyzes macromolecule GPI-AP as well as small molecules.

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From Inhibition to Degradation: Targeting the Anti-apoptotic Protein Myeloid Cell Leukemia 1(MCL1)

10.26434/chemrxiv.7722359 ◽

2019 ◽

Author(s):

James Papatzimas ◽

Evgueni Gorobets ◽

Ranjan Maity ◽

Mir Ishruna Muniyat ◽

Justin L. MacCallum ◽

...

Keyword(s):

Small Molecules ◽

E3 Ligase ◽

Myeloid Cell ◽

Cell Leukemia ◽

New Class ◽

Apoptotic Protein ◽

Family Protein ◽

Ubiquitination Pathway

<div> <div> <div> <p>Here we show the development of heterobifunctional small molecules capable of selectively targeting MCL1 using a Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitination pathway, making these PROTACs a first step toward a new class of anti-apoptotic BCL-2 family protein degraders. </p> </div> </div> </div>

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Conjugates of Classical DNA/RNA Binder with Nucleobase: Chemical, Biochemical and Biomedical Applications

Current Medicinal Chemistry ◽

10.2174/0929867325666180508090640 ◽

2019 ◽

Vol 26 (30) ◽

pp. 5609-5624

Author(s):

Dijana Saftić ◽

Željka Ban ◽

Josipa Matić ◽

Lidija-Marija Tumirv ◽

Ivo Piantanida

Keyword(s):

Molecular Weight ◽

Small Molecules ◽

Biomedical Applications ◽

Protein Targets ◽

New Class ◽

Rna Targets ◽

Covalently Linked ◽

Structural Aspects

: Among the most intensively studied classes of small molecules (molecular weight < 650) in biomedical research are small molecules that non-covalently bind to DNA/RNA, and another intensively studied class is nucleobase derivatives. Both classes have been intensively elaborated in many books and reviews. However, conjugates consisting of DNA/RNA binder covalently linked to nucleobase are much less studied and have not been reviewed in the last two decades. Therefore, this review summarized reports on the design of classical DNA/RNA binder – nucleobase conjugates, as well as data about their interactions with various DNA or RNA targets, and even in some cases protein targets are involved. According to these data, the most important structural aspects of selective or even specific recognition between small molecule and target are proposed, and where possible related biochemical and biomedical aspects were discussed. The general conclusion is that this, rather new class of molecules showed an amazing set of recognition tools for numerous DNA or RNA targets in the last two decades, as well as few intriguing in vitro and in vivo selectivities. Several lead research lines show promising advancements toward either novel, highly selective markers or bioactive, potentially druggable molecules.

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The antimicrobial potential of cannabidiol

Communications Biology ◽

10.1038/s42003-020-01530-y ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Mark A. T. Blaskovich ◽

Angela M. Kavanagh ◽

Alysha G. Elliott ◽

Bing Zhang ◽

Soumya Ramu ◽

...

Keyword(s):

Bacterial Infections ◽

Modern Medicine ◽

Gram Negative Bacteria ◽

Gram Negative ◽

New Class ◽

Clostridioides Difficile ◽

Excellent Activity ◽

Induce Resistance ◽

First Time

AbstractAntimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol’s primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the ‘urgent threat’ pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.

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Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons

Scientific Reports ◽

10.1038/s41598-021-95123-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Charles R. Midgett ◽

Kacey Marie Talbot ◽

Jessica L. Day ◽

George P. Munson ◽

F. Jon Kull

Keyword(s):

Escherichia Coli ◽

Small Molecules ◽

Family Member ◽

Shigella Flexneri ◽

Decanoic Acid ◽

Enterotoxigenic Escherichia Coli ◽

Gram Negative Bacteria ◽

Enteric Infections ◽

First Time ◽

Arac Family

AbstractEnteric infections caused by the gram-negative bacteria enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, Shigella flexneri, and Salmonella enterica are among the most common and affect billions of people each year. These bacteria control expression of virulence factors using a network of transcriptional regulators, some of which are modulated by small molecules as has been shown for ToxT, an AraC family member from V. cholerae. In ETEC the expression of many types of adhesive pili is dependent upon the AraC family member Rns. We present here the 3 Å crystal structure of Rns and show it closely resembles ToxT. Rns crystallized as a dimer via an interface similar to that observed in other dimeric AraC’s. Furthermore, the structure of Rns revealed the presence of a ligand, decanoic acid, that inhibits its activity in a manner similar to the fatty acid mediated inhibition observed for ToxT and the S. enterica homologue HilD. Together, these results support our hypothesis that fatty acids regulate virulence controlling AraC family members in a common manner across a number of enteric pathogens. Furthermore, for the first time this work identifies a small molecule capable of inhibiting the ETEC Rns regulon, providing a basis for development of therapeutics against this deadly human pathogen.

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Furil based ionic small molecules for green emitting non-doped LECs with improved color purity

New Journal of Chemistry ◽

10.1039/d1nj00155h ◽

2021 ◽

Author(s):

Jino C John ◽

Kanagaraj Shanmugasundaram ◽

Archana Puthanveedu ◽

Hariventhan Ragupathi ◽

Gopakumar Gopinadhanpillai ◽

...

Keyword(s):

Small Molecules ◽

Color Purity ◽

First Time

Two novel furil based small molecules FlBzPy and FlThPy were designed and synthesized with simple synthetic procedures for the first time for the LEC application. The optical, thermal, electronic, electroluminescent,...

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Phenotypic Susceptibility to Bevirimat in Isolates from HIV-1-Infected Patients without Prior Exposure to Bevirimat

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01784-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2345-2353 ◽

Cited By ~ 39

Author(s):

Nicolas A. Margot ◽

Craig S. Gibbs ◽

Michael D. Miller

Keyword(s):

Recombinant Viruses ◽

Gag Polyprotein ◽

New Class ◽

Major Mutation ◽

Hiv Drugs ◽

The Impact ◽

First Time ◽

Hiv 1

ABSTRACT Bevirimat (BVM) is the first of a new class of anti-HIV drugs with a novel mode of action known as maturation inhibitors. BVM inhibits the last cleavage of the Gag polyprotein by HIV-1 protease, leading to the accumulation of the p25 capsid-small peptide 1 (SP1) intermediate and resulting in noninfectious HIV-1 virions. Early clinical studies of BVM showed that over 50% of the patients treated with BVM did not respond to treatment. We investigated the impact of prior antiretroviral (ARV) treatment and/or natural genetic diversity on BVM susceptibility by conducting in vitro phenotypic analyses of viruses made from patient samples. We generated 31 recombinant viruses containing the entire gag and protease genes from 31 plasma samples from HIV-1-infected patients with (n = 21) or without (n = 10) prior ARV experience. We found that 58% of the patient isolates tested had a >10-fold reduced susceptibility to BVM, regardless of the patient's ARV experience or the level of isolate resistance to protease inhibitors. Analysis of mutants with site-directed mutations confirmed the role of the V370A SP1 polymorphism (SP1-V7A) in resistance to BVM. Furthermore, we demonstrated for the first time that a capsid polymorphism, V362I (CA protein-V230I), is also a major mutation conferring resistance to BVM. In contrast, none of the previously defined resistance-conferring mutations in Gag selected in vitro (H358Y, L363M, L363F, A364V, A366V, or A366T) were found to occur among the viruses that we analyzed. Our results should be helpful in the design of diagnostics for prediction of the potential benefit of BVM treatment in HIV-1-infected patients.

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Production and Technical Characteristics of a New Class of Amorphous Metals

MRS Proceedings ◽

10.1557/proc-400-77 ◽

1995 ◽

Vol 400 ◽

Cited By ~ 4

Author(s):

R.T. Malkhassian

Keyword(s):

Amorphous Phase ◽

Quantum Chemical ◽

New Technology ◽

Chemical Technology ◽

Quantum Level ◽

Vibrationally Excited ◽

New Class ◽

The Third ◽

Hydrogen Molecules ◽

First Time

AbstractA new technology for obtainment of amorphous single-component metals is presented.For the first time the reduction of molybdenum oxide with formation of its amorphous phase is realized in conditions of a given quantum-chemical technology by means of vibrationally excited to the third quantum level hydrogen molecules with 1.5 ± 0.2 eV energy. The evidences of formation of this nonequilibrium amorphous phase are presented along with certain physicochemical properties of the obtained amorphous molybdenum.A model is proposed for the origin of amorphous phase under the influence of nonequilibrium quantum-chemical technology.

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Palmitoylation of the Autographa californica Multicapsid Nucleopolyhedrovirus Envelope Glycoprotein GP64: Mapping, Functional Studies, and Lipid Rafts

Journal of Virology ◽

10.1128/jvi.77.11.6265-6273.2003 ◽

2003 ◽

Vol 77 (11) ◽

pp. 6265-6273 ◽

Cited By ~ 27

Author(s):

Sandy Xiaoxin Zhang ◽

Yu Han ◽

Gary W. Blissard

Keyword(s):

Cell Surface ◽

Lipid Rafts ◽

Lipid Raft ◽

Envelope Glycoprotein ◽

Cysteine Residue ◽

Autographa Californica ◽

Membrane Microdomains ◽

Sf9 Cells ◽

Wild Type ◽

Lipid Raft Microdomains

ABSTRACT Budded virions (BV) of the baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) contain a major envelope glycoprotein known as GP64, which was previously shown to be palmitoylated. In the present study, we used truncation and amino acid substitution mutations to map the palmitoylation site to cysteine residue 503. Palmitoylation of GP64 was not detected when Cys503 was replaced with alanine or serine. Palmitoylation-minus forms of GP64 were used to replace wild-type GP64 in AcMNPV, and these viruses were used to examine potential functions of GP64 palmitoylation in the context of the infection cycle. Analysis by immunoprecipitation and cell surface studies revealed that palmitoylation of GP64 did not affect GP64 synthesis or its transport to the cell surface in Sf9 cells. GP64 proteins lacking palmitoylation also mediated low-pH-triggered membrane fusion in a manner indistinguishable from that of wild-type GP64. Cells infected with viruses expressing palmitoylation-minus forms of GP64 produced infectious virions at levels similar to those from cells infected with wild-type AcMNPV. In combination, these data suggest that virus entry and exit in Sf9 cells were not significantly affected by GP64 palmitoylation. To determine whether GP64 palmitoylation affected the association of GP64 with membrane microdomains, the potential association of GP64 with lipid raft microdomains was examined. These experiments showed that: (i) AcMNPV-infected Sf9 cell membranes contain lipid raft microdomains, (ii) GP64 association with lipid rafts was not detected in infected Sf9 cells, and (iii) GP64 palmitoylation did not affect the apparent exclusion of GP64 from lipid raft microdomains.

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Graphite/UPE Nanocomposite: Transport, Thermal, Mechanical and Viscoelastic Properties

Diffusion Foundations ◽

10.4028/www.scientific.net/df.23.201 ◽

2019 ◽

Vol 23 ◽

pp. 201-212

Author(s):

Shivkumari Panda ◽

Dibakar Behera ◽

Tapan Kumar Bastia

Keyword(s):

Transport Properties ◽

Unsaturated Polyester ◽

Homogeneous Distribution ◽

Thermo Gravimetric ◽

New Class ◽

The Matrix ◽

Novel Method ◽

Water Transport Properties ◽

First Time

This chapter presents the preparation and characterization of some unique properties of nanocomposites by dispersing graphite flakes in commercial unsaturated polyester (UPE) matrix. The composite was prepared by a novel method with the use of solvent swelling technique. Three different specimens of UPE/graphite nanocomposites were fabricated with addition of 1, 2 and 3 wt% of graphite flakes. Except mechanical, viscoelastic and thermo gravimetric properties, transport properties like electrical conductivity, thermal conductivity and water transport properties were studied for the first time. Graphite flakes propose enhanced properties to the composites suggesting homogeneous distribution of the nanofiller in the matrix and strong interaction with the matrix. 2wt% nanofiller loading showed superior essential characteristics and after that the properties reduced may be due to the nucleating tendency of the nanofiller particles. The XRD pattern showed the compatibility of the graphite flakes by introducing a peak around 26.550 in the nanocomposites. SEM Properties are also in agreement with the compatibility. Nanocomposite with 2wt% graphite also showed remarkable enhancement in transport, mechanical, viscoelastic and thermo gravimetric properties. So by introduction of a small quantity of graphite endow the new class of multiphase nanocomposites with inimitable structure and tremendous application.

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