18 Aug 13:09
by Paola Nol Bernardino
Vaccine. 2023 Jul 15:S0264-410X(23)00830-7. doi: 10.1016/j.vaccine.2023.07.018. Online ahead of print.
ABSTRACT
Low and very-low-birth-weight (V/LBW) neonates are highly susceptible to bacterial sepsis and meningitis. Bacterial infections caused by Staphylococcus aureus can be particularly dangerous for neonates and can result in high mortality and long-term disabilities.Antibody-based strategies have been attempted to protect V/LBW neonates against staphylococcal disease. However, these efforts have so far been unsuccessful. Failures were attributed to the immaturity of the neonatal immune system but did not account for the anti-opsonic activity of Staphylococcal protein A (SpA). Here we show that monoclonal antibody 3F6, which blocks SpA activity, promotes complement-dependent cell-mediated phagocytosis of S. aureus in human umbilical cord blood. A substitution in the crystallizable fragment (Fc) region of 3F6 that enhances recruitment of complement component C1q further increases the phagocytic activity of cord blood. Our data demonstrate that the neonatal immune system possesses bactericidal activity that can be harnessed by antibodies that circumvent a key innate immune strategy of S. aureus.
PMID:37455161 | DOI:10.1016/j.vaccine.2023.07.018
17 Aug 19:55
by Aleksandra Cecylia Stasiak
J Biol Chem. 2023 Jul 20:105076. doi: 10.1016/j.jbc.2023.105076. Online ahead of print.
ABSTRACT
The bacterial cell wall consists of a three-dimensional peptidoglycan layer, composed of peptides linked to the sugars N-acetylmuramic acid (MurNAc) and GlcNAc. Unlike other bacteria, the pathogenic Tannerella forsythia, a member of the red complex group of bacteria associated with the late stages of periodontitis, lacks biosynthetic pathways for MurNAc production and therefore obtains MurNAc from the environment. Sugar kinases play a crucial role in the MurNAc recycling process, activating the sugar molecules by phosphorylation. In this study, we present the first crystal structures of a MurNAc kinase, called murein sugar kinase (MurK), in its unbound state as well as in complexes with the ATP analogue β-γ-methylene adenosine triphosphate (AMP-PCP) and with MurNAc. We also determined the crystal structures of K1058, a paralogous MurNAc kinase of T. forsythia, in its unbound state and in complex with MurNAc. We identified the active site and residues crucial for MurNAc specificity as the less bulky side chains of S133, P134, and L135, which enlarge the binding cavity for the lactyl ether group, unlike the glutamate or histidine residues present in structural homologues. In establishing the apparent kinetic parameters for both enzymes, we showed a comparable affinity for MurNAc (Km 180 μM and 30 μM for MurK and K1058, respectively), with MurK being over two hundred times faster than K1058 (Vmax 80 and 0.34 μmol min-1 mg-1, respectively). These data might support a structure-guided approach to development of inhibitory MurNAc analogues for pathogen MurK enzymes.
PMID:37481208 | DOI:10.1016/j.jbc.2023.105076
17 Aug 19:46
by Jaypalsing Ingle,
Bibhas Das,
Keshav Chaudhary,
Anirban Mondal,
Sudipta Basu
Highly substituted small molecule modular oxazoles having dual intramolecular H-bonding, aggregated in water to instigate aggregation-induced emission (AIE) properties through restriction in motion leading to illuminate sub-cellular ER, mitochondria and lysosomes.
Abstract
Organelles are the working hubs of the cells. Hence, visualizing these organelles inside the cells is highly important for understanding their roles in pathological states and development of therapeutic strategies. Herein, we report the development of a novel highly substituted oxazoles with modular scaffolds (AIE-ER, AIE-Mito, and AIE-Lyso), which can home into endoplasmic reticulum (ER), mitochondria, and lysosomes inside the cells. These oxazoles showed remarkable aggregation-induced emission (AIE) property in water and in the solid state due to dual intramolecular H-bonding, which was confirmed by pH- and temperature-dependent fluorescence studies followed by molecular dynamics (MD) simulations and density functional theory (DFT) calculations. Confocal laser scanning microscopy studies revealed that AIE-ER, AIE-Mito, and AIE-Lyso efficiently homed into ER, mitochondria and lysosomes, respectively, in the HeLa cervical cancer cells and non-cancerous human retinal pigment epithelial RPE-1 cells within 3 h without showing any toxicity to the cells with high sub-cellular photostability. To the best of our knowledge, this is the first report of highly substituted oxazole-based small molecule AIEgens for organelle imaging. We anticipate these novel AIEgens have promise to image sub-cellular organelles in different diseased states as well as understanding the inter-organelle interactions towards the development of novel therapeutics.
17 Aug 19:43
by Christopher Vennard
J Med Chem. 2023 Aug 10;66(15):10238-10240. doi: 10.1021/acs.jmedchem.3c01219. Epub 2023 Jul 21.
ABSTRACT
Vancomycin-like drugs target peptidoglycan (PG) via binding to C-terminal d-Ala-d-Ala dipeptide. An engineered vancomycin has enhanced affinity for the PG stem peptide, due to probable interactions with a third residue, meso-diaminopimelic acid, in the PG. This engineered vancomycin displays enhanced killing of mycobacteria.
PMID:37477251 | DOI:10.1021/acs.jmedchem.3c01219
17 Aug 19:09
by Koji Kadota,
Toshiki Mikami,
Ai Kohata,
Jumpei Morimoto,
Shinsuke Sando,
Kohsuke Aikawa,
Takashi Okazoe
Tripeptides bearing RF-AAs were synthesized and the hydrophilic dye Alexa Fluor 647 (AF) was employed as a hydrophilic model cargo. AF-RF-tripeptides formed nanoparticles in aqueous media and were taken up by cells. Both the length of the RF group and the absolute configuration of the RF-AAs significantly affected the size of the nanoparticles, which is an important factor for efficient cellular uptake by endocytosis.
Abstract
With an increasing demand for macromolecular biotherapeutics, the issue of their poor cell-penetrating abilities requires viable and relevant solutions. Herein, we report tripeptides bearing an amino acid with a perfluoroalkyl (RF) group adjacent to the α-carbon. RF-containing tripeptides were synthesized and evaluated for their ability to transport a conjugated hydrophilic dye (Alexa Fluor 647) into the cells. RF-containing tripeptides with the fluorophore showed high cellular uptake efficiency and none of them were cytotoxic. Interestingly, we demonstrated that the absolute configuration of perfluoroalkylated amino acids (RF-AAs) affects not only nanoparticle formation but also the cell permeability of the tripeptides. These novel RF-containing tripeptides are potentially useful as short and noncationic cell-penetrating peptides (CPPs).
16 Aug 21:09
by Christopher John Harding
Nature Chemical Biology, Published online: 29 June 2023; doi:10.1038/s41589-023-01373-8
The secreted aminopeptidase Pseudomonas aeruginosa aminopeptidase (PaAP) is required for nutrient recycling in biofilms. Using the information from protein structure and kinetics, a potent cyclic peptide inhibitor for PaAP was designed that killed cells in late-stage biofilms.
16 Aug 20:57
by James Chen
Nature, Published online: 26 July 2023; doi:10.1038/s41586-023-06366-0
Proteins of the Mycobacterium smegmatis Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the impermeable mycobacterial cell envelope.
16 Aug 20:52
by Mariana Lenharo
Nature, Published online: 10 August 2023; doi:10.1038/d41586-023-02528-2
Clinical-trial data suggest that semaglutide, sold under the name Wegovy, slashes risk of heart attacks and other cardiovascular incidents.
16 Aug 20:45
by Harden, S. A.
Oxidative phosphorylation, the combined activities of the electron transport chain (ETC) and adenosine triphosphate (ATP) synthase, has emerged as a valuable target for antibiotics to treat infection with Mycobacterium tuberculosis and related pathogens. In oxidative phosphorylation, the ETC establishes a transmembrane electrochemical proton gradient that powers ATP synthesis. Monitoring oxidative phosphorylation with luciferase-based detection of ATP synthesis or measurement of oxygen consumption can be technically challenging and expensive. These limitations reduce the utility of these methods for characterization of mycobacterial oxidative phosphorylation inhibitors. Here we show that fluorescence-based measurement of acidification of inverted membrane vesicles (IMVs) can detect and distinguish between inhibition of the ETC, inhibition of ATP synthase, and non-specific membrane uncoupling. In this assay, IMVs from M. smegmatis are acidified either through the activity of the ETC or ATP synthase, the latter modified genetically to allow it to serve as an ATP-driven proton pump. Acidification is monitored by fluorescence from 9-amino-6-chloro-2-methoxyacridine, which accumulates and quenches in acidified IMVs. Non-specific membrane uncouplers prevent both succinate- and ATP-driven IMV acidification. In contrast, the ETC Complex III2IV2 inhibitor telacebec (Q203) prevents succinate-driven acidification but not ATP-driven acidification and the ATP synthase inhibitor bedaquiline prevents ATP-driven acidification but not succinate-driven acidification. We use the assay to show that, as proposed previously, lansoprazole sulfide is an inhibitor of Complex III2IV2 while thioridazine uncouples the mycobacterial membrane non-specifically. Overall, the assay is simple, low cost, and scalable, which will make it useful for identifying and characterizing new mycobacterial oxidative phosphorylation inhibitors.
16 Aug 20:44
by Pang, Y.
Red fluorescent protein (RFP) derived indicators are popular due to advantages such as increased imaging depth and reduced autofluorescence and cytotoxicity. However, most RFP-based indicators have low brightness and are susceptible to blue-light-induced photoactivation. In this study, we aimed to overcome the limitations of existing red fluorescent indicators. We utilized mScarlet-I, a highly bright and robust monomeric RFP, to develop a circularly permuted variant called cpmScarlet. We further engineered cpmScarlet into a novel red fluorescent indicator specifically for hydrogen peroxide (H2O2), a crucial reactive oxygen species (ROS) involved in redox signaling and oxidative stress. The resultant indicator, SHRIMP (mScarlet-derived H2O2 Redox Indicator with Minimal Photoactivation), exhibited excitation and emission peaks at [~]570 and 595 nm, respectively, and demonstrated a maximum five-fold fluorescence turn-off response to H2O2. Importantly, SHRIMP was not susceptible to blue-light-induced photoactivation and showed high brightness both in its purified protein form and when expressed in mammalian cells. We successfully employed SHRIMP to visualize H2O2 dynamics in mammalian cells with exogenously added H2O2 and in activated macrophages. Additionally, we demonstrated its utility for multiparameter imaging by co-expressing SHRIMP with GCaMP6m, a green fluorescent calcium indicator, enabling simultaneous monitoring of H2O2 and calcium dynamics in mammalian cells in response to thapsigargin (TG) and epidermal growth factor (EGF) stimulation. Furthermore, we expressed SHRIMP in isolated primary mouse islet tissue, and SHRIMP exhibited excellent brightness and capability for effective detection of H2O2 production during streptozotocin (STZ)-induced {beta}-cell damage. This study successfully transformed mScarlet-I, a bright and robust monomeric RFP, into a circularly permuted variant (cpmScarlet) and developed the first cpmScarlet-based genetically encoded fluorescent indicator called SHRIMP. SHRIMP exhibits high brightness and insensitivity to photoactivation and is a valuable tool for real-time monitoring of H2O2 dynamics in various biological systems. Further research may yield an expanded family of cpmScarlet-based red fluorescent indicators with enhanced photophysical properties.
16 Aug 20:40
by Javier Narbona
Biomolecules. 2023 Jun 26;13(7):1042. doi: 10.3390/biom13071042.
ABSTRACT
Immunotoxins (ITXs) are chimeric molecules that combine the specificity of a targeting domain, usually derived from an antibody, and the cytotoxic potency of a toxin, leading to the selective death of tumor cells. However, several issues must be addressed and optimized in order to use ITXs as therapeutic tools, such as the selection of a suitable tumor-associated antigen (TAA), high tumor penetration and retention, low kidney elimination, or low immunogenicity of foreign proteins. To this end, we produced and characterized several ITX designs, using a nanobody against EGFR (VHH 7D12) as the targeting domain. First, we generated a nanoITX, combining VHH 7D12 and the fungal ribotoxin α-sarcin (αS) as the toxic moiety (VHHEGFRαS). Then, we incorporated a trimerization domain (TIEXVIII) into the construct, obtaining a trimeric nanoITX (TriVHHEGFRαS). Finally, we designed and characterized a bispecific ITX, combining the VHH 7D12 and the scFv against GPA33 as targeting domains, and a deimmunized (DI) variant of α-sarcin (BsITXαSDI). The results confirm the therapeutic potential of α-sarcin-based nanoITXs. The incorporation of nanobodies as target domains improves their therapeutic use due to their lower molecular size and binding features. The enhanced avidity and toxic load in the trimeric nanoITX and the combination of two different target domains in the bispecific nanoITX allow for increased antitumor effectiveness.
PMID:37509078 | PMC:PMC10377705 | DOI:10.3390/biom13071042
16 Aug 20:25
by Mark Peplow
Nature Biotechnology, Published online: 05 July 2023; doi:10.1038/s41587-023-01860-2
Bioorthogonal click chemistry is being used in patients to help target cancer medicines and diagnostic imaging agents
16 Aug 20:25
by Hongcheng Mai
Nature Biotechnology, Published online: 10 July 2023; doi:10.1038/s41587-023-01846-0
Whole mice are immunolabeled with standard antibodies using wildDISCO.
16 Aug 20:24
by Elie Dolgin
Nature Biotechnology, Published online: 17 July 2023; doi:10.1038/s41587-023-01880-y
Harnessing the unusual biology of bats, researchers aim to turn drug discovery upside-down.
31 Jul 19:21
by Resat Aksakal
Chem Sci. 2023 May 22;14(24):6572-6578. doi: 10.1039/d3sc01507f. eCollection 2023 Jun 21.
ABSTRACT
Antibody-recruiting molecules represent a novel class of therapeutic agents that mediate the recruitment of endogenous antibodies to target cells, leading to their elimination by the immune system. Compared to single-ligand copies, macromolecular scaffolds presenting multiple copies of an antibody-binding ligand offer advantages in terms of increased complex avidity. In this study, we describe the synthesis of sequence-defined macromolecules designed for antibody recruitment, utilising dinitrophenol (DNP) as a model antibody-recruiting motif. The use of discrete macromolecules gives access to varying the spacing between DNP motifs while maintaining the same chain length. This characteristic enables the investigation of structure-dependent binding interactions with anti-DNP antibodies. Through solid-phase thiolactone chemistry, we synthesised a series of oligomers with precisely localised DNP motifs along the backbone and a terminal biotin motif for surface immobilisation. Utilising biolayer interferometry analysis, we observed that oligomers with adjacent DNP motifs exhibited enhanced avidity for anti-DNP antibodies. Molecular modelling provided insights into the structures and dynamics of the various macromolecules, shedding light on the accessibility of the ligands to the antibodies. Overall, our findings highlight that the use of sequence-defined macromolecules can contribute to our understanding of structure-activity relationships and provide insights for the design of novel antibody-recruiting therapeutic agents.
PMID:37350815 | PMC:PMC10284026 | DOI:10.1039/d3sc01507f
31 Jul 19:19
by Yusei Nakaya,
Miu Uchiike,
Mayuko Hattori,
Momoka Moriyama,
Kimihiro Abe,
Ella Kim,
Patrick Eichenberger,
Daisuke Imamura,
Tsutomu Sato
The polysaccharide layer of Bacillus subtilis spores contributes to the diffusion of spores in water-rich environments by making the spore surface more hydrophilic. This study revealed that polysaccharides are anchored to the surface of spores via the crust protein CgeA at threonine 112 (T112).
Abstract
The Bacillus subtilis spore is composed of a core, containing chromosomal DNA, surrounded by a cortex layer made of peptidoglycan, and a coat composed of concentric proteinaceous layers. A polysaccharide layer is added to the spore surface, and likely anchored to the crust, the coat outermost layer. However, the identity of the coat protein(s) to which the spore polysaccharides (SPS) are attached is uncertain. First, we showed that the crust proteins CotVWXYZ and CgeA were all contained in the peeled SPS layer obtained from a strain missing CotE, the outer coat morphogenetic protein, suggesting that the SPS is indeed bound to at least one of the spore surface proteins. Second, CgeA is known to be located at the most downstream position in the crust assembly pathway. An analysis of truncated variants of CgeA suggested that its N-terminal half is required for localization to the spore surface, while its C-terminal half is necessary for SPS addition. Third, an amino acid substitution strategy revealed that SPS was anchored at threonine 112 (T112), which constitutes a probable O-glycosylation site on CgeA. Our results indicated that CgeA is a glycoprotein required to initiate SPS assembly and serves as an anchor protein linking the crust and SPS layers.
31 Jul 14:02
by Heloisa V Pereira-Maróstica
Environ Toxicol Pharmacol. 2023 Jul 11;102:104217. doi: 10.1016/j.etap.2023.104217. Online ahead of print.
ABSTRACT
Chlorhexidine (CHX) is an over-the-counter antiseptic amply used by the population. There are reports that CHX acts in mitochondria as an uncoupler and inhibitor. The purpose of this study was to investigate the short-term effects of CHX on hepatic metabolic pathways linked to energy metabolism in the perfused rat liver. The compound inhibited both glucose synthesis and the urea cycle. Oxygen consumption was raised at low concentrations (up to 10 μM) and diminished at higher ones. A pronounced diminution in the cellular ATP content was observed. Conversely, CHX stimulated glycolysis and enhanced leakage of cellular enzymes (lactate dehydrogenase and fumarase). In isolated mitochondria, this antiseptic inhibited pyruvate carboxylation, oxidases, and oxygen uptake at very low concentrations (2 μM) and promoted uncoupling. The results described herein raise great concerns about the safety of CHX, as the observed effects can induce hypoglycemia, lactic acidosis, ammonemia as well as cell membrane disruption.
PMID:37442400 | DOI:10.1016/j.etap.2023.104217
31 Jul 14:01
by Tao Zhang
Life Sci. 2023 Jul 15;329:121943. doi: 10.1016/j.lfs.2023.121943. Online ahead of print.
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide, ranging from liver steatosis to nonalcoholic steatohepatitis, which ultimately progresses to fibrosis, cirrhosis, and hepatocellular carcinoma. Individuals with NAFLD have a higher risk of developing cardiovascular and extrahepatic cancers. Despite the great progress being made in understanding the pathogenesis and the introduction of new pharmacological targets for NAFLD, no drug or intervention has been accepted for its management. Recent evidence suggests that NAFLD may be a mitochondrial disease, as mitochondrial dysfunction is involved in the pathological processes that lead to NAFLD. In this review, we describe the recent advances in our understanding of the mechanisms associated with mitochondrial dysfunction in NAFLD progression. Moreover, we discuss recent advances in the efficacy of mitochondria-targeted compounds (e.g., Mito-Q, MitoVit-E, MitoTEMPO, SS-31, mitochondrial uncouplers, and mitochondrial pyruvate carrier inhibitors) for treating NAFLD. Furthermore, we present some medications currently being tested in clinical trials for NAFLD treatment, such as exercise, mesenchymal stem cells, bile acids and their analogs, and antidiabetic drugs, with a focus on their efficacy in improving mitochondrial function. Based on this evidence, further investigations into the development of mitochondria-based agents may provide new and promising alternatives for NAFLD management.
PMID:37454757 | DOI:10.1016/j.lfs.2023.121943
31 Jul 13:57
by Liyan Zhang, Peiyuan Wang, Xue-Quan Zhou, Ludovic Bretin, Xiaolong Zeng, Yurii Husiev, Ehider A. Polanco, Gangyin Zhao, Lukas S. Wijaya, Tarita Biver, Sylvia E. Le Dévédec, Wen Sun, and Sylvestre Bonnet
Journal of the American Chemical Society
DOI: 10.1021/jacs.3c04855
31 Jul 12:50
by Magdalena Szczesna
Res Sq. 2023 Jul 12:rs.3.rs-2986327. doi: 10.21203/rs.3.rs-2986327/v1. Preprint.
ABSTRACT
Pathogenic bacteria have evolved diverse mechanisms to counteract cell-autonomous immunity, which otherwise guards both immune and non-immune cells from the onset of an infection 1,2 . The versatile immunity protein Ring finger protein 213 (RNF213) 3-6 mediates the non-canonical ester-linked ubiquitylation of lipopolysaccharide (LPS), marking bacteria that sporadically enter the cytosol for destruction by antibacterial autophagy 4 . However, whether cytosol-adapted pathogens are ubiquitylated on their LPS and whether they escape RNF213-mediated immunity, remains unknown. Here we show that Burkholderia deubiquitylase (DUB), TssM 7-9 , is a potent esterase that directly reverses the ubiquitylation of LPS. Without TssM, cytosolic Burkholderia became coated in polyubiquitin and autophagy receptors in an RNF213-dependent fashion. Whereas the expression of TssM was sufficient to enable the replication of the non-cytosol adapted pathogen Salmonella, we demonstrate that Burkholderia has evolved a multi-layered defence system to proliferate in the host cell cytosol, including a block in antibacterial autophagy 10-12 . Structural analysis provided insight into the molecular basis of TssM esterase activity, allowing it to be uncoupled from isopeptidase function. TssM homologs conserved in another Gram-negative pathogen also reversed non-canonical LPS ubiquitylation, establishing esterase activity as a bacterial virulence mechanism to subvert host cell-autonomous immunity.
PMID:37503018 | PMC:PMC10371091 | DOI:10.21203/rs.3.rs-2986327/v1
28 Jul 20:40
by Zahra Shadman
Infect Disord Drug Targets. 2023;23(5):e290323215113. doi: 10.2174/1871526523666230329104537.
ABSTRACT
BACKGROUND: Pseudomonas (P.) aeruginosa is one of the leading causes of nosocomial infections. The pathogenicity of P. aeruginosa is related to its inherent antimicrobial resistance and the diverse virulence factors of this bacterium. Owing to the specific role of exotoxin A in P. aeruginosa pathogenesis, it is known as a promising therapeutic candidate to develop antibodies as an alternative to antibiotics.
OBJECTIVE: The present study aimed to validate the interaction between a single-chain fragment variable (scFv) antibody identified from an scFv phage library against domain I exotoxin A by bioinformatic tools.
METHODS: For this, several bioinformatics tools, including Ligplot, Swiss PDB viewer (SPDBV), PyMOL, I-TASSER, Gromacs, and ClusPro servers were used to evaluate the interaction of scFv antibody with P. aeruginosa exotoxin A. The I-TASSER server was utilized to predict the function and structure of proteins. The interaction of two proteins was analyzed using ClusPro tools. The best docking results were further analyzed with Ligplot, Swiss PDB viewer, and PyMOL. Consequently, molecular dynamics simulation was utilized to predict the stability of the secondary structure of the antibody and the binding energy of the scFv antibody to the domain I of exotoxin A.
RESULTS: As a result, we demonstrated that data from computational biology could provide proteinprotein interaction information between scFv antibody/domain I exotoxin A and offers new insights into antibody development and therapeutic expansion.
CONCLUSION: In summary, a recombinant human scFv capable of neutralizing P. aeruginosa exotoxin A is recommended as a promising treatment for infections caused by P. aeruginosa.
PMID:36999425 | DOI:10.2174/1871526523666230329104537
28 Jul 20:38
by Mingming Qi, Hui Zhong, Zhaoyan Cheng, Shujie Chen, Han Xiao, Jing Shang, Li Chen, and Jianbo Sun
Journal of Medicinal Chemistry
DOI: 10.1021/acs.jmedchem.3c00822
28 Jul 20:32
by Koji Kadota,
Toshiki Mikami,
Ai Kohata,
Jumpei Morimoto,
Shinsuke Sando,
Kohsuke Aikawa,
Takashi Okazoe
Tripeptides bearing RF-AAs were synthesized and the hydrophilic dye Alexa Fluor 647 (AF) was employed as a hydrophilic model cargo. AF-RF-tripeptides formed nanoparticles in aqueous media and were taken up by cells. Both the length of the RF group and the absolute configuration of the RF-AAs significantly affected the size of the nanoparticles, which is an important factor for efficient cellular uptake by endocytosis.
Abstract
With an increasing demand for macromolecular biotherapeutics, the issue of their poor cell-penetrating abilities requires viable and relevant solutions. Herein, we report tripeptides bearing an amino acid with a perfluoroalkyl (RF) group adjacent to the α-carbon. RF-containing tripeptides were synthesized and evaluated for their ability to transport a conjugated hydrophilic dye (Alexa Fluor 647) into the cells. RF-containing tripeptides with the fluorophore showed high cellular uptake efficiency and none of them were cytotoxic. Interestingly, we demonstrated that the absolute configuration of perfluoroalkylated amino acids (RF-AAs) affects not only nanoparticle formation but also the cell permeability of the tripeptides. These novel RF-containing tripeptides are potentially useful as short and noncationic cell-penetrating peptides (CPPs).
28 Jul 12:40
by Thomas A King
Chem Commun (Camb). 2023 Jul 26. doi: 10.1039/d3cc02980h. Online ahead of print.
ABSTRACT
Numerous antibody-drug conjugate (ADC) linker technologies exist for the synthesis of ADCs with drug-to-antibody ratios (DARs) being an even integer (typically 2, 4 or 8). However, ADCs with odd-integer DARs are significantly harder to synthesise. Here, we report the synthesis of ADCs loaded with a single warhead, using TetraDVP linkers which simultaneously re-bridge all four interchain disulfides of an IgG1 antibody.
PMID:37492000 | DOI:10.1039/d3cc02980h
17 Jul 19:56
by Rahman, S.
Staphylococcus aureus has become a significant cause of health risks in humankind. Staphylococcal superantigens (SAgs) or enterotoxins are the key virulent factors that can exhibit acute diseases to severe life-threatening conditions. Recent literature reports S. aureus has steadily gained new enterotoxin genes over the past few decades. In spite of current knowledge of the established SAgs, several questions on these putative enterotoxins are still remaining unanswered. Keeping that in mind, this study sheds light on a putative enterotoxin SEl26 to characterize its structural and functional properties. In-silico analyses indicate its close relation with the conventional SAgs, especially the zinc-binding SAgs. Additionally, important residues have been predicted that are vital for T-Cell receptor (TcR) and major histocompatibility complex class II (MHC-II) interaction and compared them with established SAgs. Besides, our biochemical analyses exhibited the binding of this putative enterotoxin with MHC-II, followed by regulating pro-inflammatory and anti-inflammatory cytokines.
17 Jul 19:55
by Stefano Gambato, Ottavia Bellotto, Mario Mardirossian, Adriana Di Stasi, Renato Gennaro, Sabrina Pacor, Andrea Caporale, Federico Berti, Marco Scocchi, and Alessandro Tossi
Bioconjugate Chemistry
DOI: 10.1021/acs.bioconjchem.2c00467
17 Jul 19:53
Researchers from the University of St Andrews have developed peptides that can help combat bacteria growing in biofilms, which occur in up to 80% of human infections.
17 Jul 17:45
by Wenjun Zhan,
Lingling Xu,
Zhiyu Liu,
Xiaoyang Liu,
Ge Gao,
Tiantian Xia,
Xiaotong Cheng,
Xianbao Sun,
Fu-Gen Wu,
Qian Yu,
Gaolin Liang
A strategy of tandem guest-host-receptor recognitions was proposed to precisely guide ciprofloxacin to effectively eliminate intracellular S. aureus. Cip-CBT-Ada/CD-M was obtained through guest-host recognition. After targeting S. aureus-infected macrophages via ligand-receptor recognition, Cip-CBT-Ada/CD-M underwent intracellular caspase-1-triggered self-assembly to form ciprofloxacin nanoparticle, leading to enhanced antibacterial efficiency.
Abstract
Staphylococcus aureus (S. aureus) is able to hide within host cells to escape immune clearance and antibiotic action, causing life-threatening infections. To boost the therapeutic efficacy of antibiotics, new intracellular delivery approaches are urgently needed. Herein, by rational design of an adamantane (Ada)-containing antibiotic-peptide precursor Ada-Gly-Tyr-Val-Ala-Asp-Cys(StBu)-Lys(Ciprofloxacin)-CBT (Cip-CBT-Ada), we propose a strategy of tandem guest-host-receptor recognitions to precisely guide ciprofloxacin to eliminate intracellular S. aureus. Via guest-host recognition, Cip-CBT-Ada is decorated with a β-cyclodextrin-heptamannoside (CD-M) derivative to yield Cip-CBT-Ada/CD-M, which is able to target mannose receptor-overexpressing macrophages via multivalent ligand-receptor recognition. After uptake, Cip-CBT-Ada/CD-M undergoes caspase-1 (an overexpressed enzyme during S. aureus infection)-initiated CBT-Cys click reaction to self-assemble into ciprofloxacin nanoparticle Nano-Cip. In vitro and in vivo experiments demonstrate that, compared with ciprofloxacin or Cip-CBT-Ada, Cip-CBT-Ada/CD-M shows superior intracellular bacteria elimination and inflammation alleviation efficiency in S. aureus-infected RAW264.7 cells and mouse infection models, respectively. This work provides a supramolecular platform of tandem guest-host-receptor recognitions to precisely guide antibiotics to eliminate intracellular S. aureus infection efficiently.
17 Jul 13:19
by Sitara Niranjan
Front Endocrinol (Lausanne). 2023 Jun 15;14:1193373. doi: 10.3389/fendo.2023.1193373. eCollection 2023.
ABSTRACT
Diabetes mellitus is a metabolic disease clinically-characterized as acute and chronic hyperglycemia. It is emerging as one of the common conditions associated with incident liver disease in the US. The mechanism by which diabetes drives liver disease has become an intense topic of discussion and a highly sought-after therapeutic target. Insulin resistance (IR) appears early in the progression of type 2 diabetes (T2D), particularly in obese individuals. One of the co-morbid conditions of obesity-associated diabetes that is on the rise globally is referred to as non-alcoholic fatty liver disease (NAFLD). IR is one of a number of known and suspected mechanism that underlie the progression of NAFLD which concurrently exhibits hepatic inflammation, particularly enriched in cells of the innate arm of the immune system. In this review we focus on the known mechanisms that are suspected to play a role in the cause-effect relationship between hepatic IR and hepatic inflammation and its role in the progression of T2D-associated NAFLD. Uncoupling hepatic IR/hepatic inflammation may break an intra-hepatic vicious cycle, facilitating the attenuation or prevention of NAFLD with a concurrent restoration of physiologic glycemic control. As part of this review, we therefore also assess the potential of a number of existing and emerging therapeutic interventions that can target both conditions simultaneously as treatment options to break this cycle.
PMID:37396181 | PMC:PMC10313404 | DOI:10.3389/fendo.2023.1193373
17 Jul 13:18
by Yoshikazu Kawai
Nat Commun. 2023 Jul 11;14(1):4123. doi: 10.1038/s41467-023-39723-8.
ABSTRACT
Inhibition of bacterial cell wall synthesis by antibiotics such as β-lactams is thought to cause explosive lysis through loss of cell wall integrity. However, recent studies on a wide range of bacteria have suggested that these antibiotics also perturb central carbon metabolism, contributing to death via oxidative damage. Here, we genetically dissect this connection in Bacillus subtilis perturbed for cell wall synthesis, and identify key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species through cellular respiration. Our results also reveal the critical role of iron homeostasis for the oxidative damage-mediated lethal effects. We show that protection of cells from oxygen radicals via a recently discovered siderophore-like compound uncouples changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. Phase paling appears to be closely associated with lipid peroxidation.
PMID:37433811 | PMC:PMC10336097 | DOI:10.1038/s41467-023-39723-8