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An efficient and scalable synthesis of potent TLR2 agonistic PAM₂CSK₄.

ABSTRACT: Diacylated PAM₂CSK₄, a highly expensive lipopeptide with desirable aqueous solubility and a broad spectrum of cytokine/chemokine induction is a most potent dual (human and murine) Toll-Like Receptor-2 (TLR2) agonist. Besides such thrilling characteristics, its synthetic process is not reported in the literature. The present report describes an efficient and scalable 20 step synthesis of PAM₂CSK₄ in good yield (all steps > 60%) along with a clear description of the hindrances and easy solutions adopted in each step. Overall, a convergent synthetic approach was adopted involving synthesis of appropriately protected starting materials, synthesis of a key backbone skeleton PAM₂CS, synthesis of a tetralysine fragment and the final coupling to yield PAM₂CSK₄. Tedious column chromatography was avoided on a large scale in many steps.

SUBMITTER: Kaur A

PROVIDER: S-EPMC9078680 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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An efficient and scalable synthesis of potent TLR2 agonistic PAM2CSK4.

Kaur Arshpreet A Poonam Patil Madhuri T MT Mehta Surinder K SK Mehta Surinder K SK Salunke Deepak B DB

RSC advances 20180305 18

Diacylated PAM2CSK4, a highly expensive lipopeptide with desirable aqueous solubility and a broad spectrum of cytokine/chemokine induction is a most potent dual (human and murine) Toll-Like Receptor-2 (TLR2) agonist. Besides such thrilling characteristics, its synthetic process is not reported in the literature. The present report describes an efficient and scalable 20 step synthesis of PAM2CSK4 in good yield (all steps > 60%) along with a clear descri ...[more]

PMID: 35540846

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Siegesbeckia pubescens Makino inhibits Pam3CSK4-induced inflammation in RAW 264.7 macrophages through suppressing TLR1/TLR2-mediated NF-κB activation.

Project description:BackgroundSiegesbeckia pubescens Makino (SP) is one of the important plant origins for the anti-inflammatory Chinese herbal medicine of Siegesbeckiae Herba. The current investigations indicated that the anti-inflammatory effects of SP were associated with the toll-like receptors (TLRs)-mediated nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways.MethodsRaw 264.7 macrophages were pretreated with the 50% ethanol extract of SP (SPE, 50-200 µg/mL) and then co-treated with Pam3CSK4 (200 ng/mL) for another 12 h. The inhibitory effect of SPE on Pam3CSK4-stimulated NO release and post-inflammatory cytokines secretions were determined using Griess reagent and Elisa kits, respectively. The influence of SPE on NF-κB and MAPKs signaling relevant proteins was measured by Western blotting analysis, while the intracellular nitric oxide (NO) generation and NF-κB/p65 nuclear translocation were determined using Leica TCS SP8 laser scanning confocal microscope. Moreover, the effect of SPE on luciferase reporter gene in NF-κB-luc DNA transfected raw 264.7 cells was determined using the Dual-Glo luciferase assay system kit.ResultsSPE dose-dependently (50-200 µg/mL) attenuated Pam3CSK4-induced NO release, post-inflammatory cytokines (IL-6, TNF-α and MCP-1) secretions and intracellular NO generation in raw 264.7 cells. Biologically, SPE suppressed Pam3CSK4-induced expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phosphorylation of NF-κB/p65 and IκBα, but did not significantly show effect on the proteins involved in MAPKs signaling (p38, ERK and JNK). The results were further confirmed by NF-κB-luc reporter gene assay and p65 nuclear translocation assay.ConclusionsIn conclusion, SPE ameliorated Pam3CSK4-induced inflammation in raw 264.7 cells through suppressing TLR 1/2-mediated NF-κB activation.

| S-EPMC6034227 | biostudies-literature

Stereoisomeric Pam2CS based TLR2 agonists: synthesis, structural modelling and activity as vaccine adjuvants.

Project description:Lipopeptides including diacylated Pam2CSK4 as well as triacylated Pam3CSK4 act as ligands of toll-like receptor (TLR)-2, a promising target for the development of vaccine adjuvants. The highly investigated Pam2CSK4 and Pam3CSK4, despite their aqueous solubility have not performed well as vaccine adjuvants which may be attributable to potential denaturation of protein antigens by these cationic surfactant-like lipopeptides. In the present investigation, we synthesized (R), (S) and racemic Pam2CS(OMe) analogs and their N-acetyl derivatives without the tetralysine component to systematically investigate the effect of stereochemistry at the thio-glycerol lipopeptide core of these lipopeptide based TLR2 agonists. The resulting compounds were compared using TLR2 reporter cell-based assays and the ability of the synthesized lipopeptides to stimulate cytokine production (IL-6, IL-10 and TNF-α) by freshly collected human PBMCs and CD40 and CD86 expressions by mouse spleen cells was also investigated. Notably, few synthesized lipopeptides were found to be potent TLR2/6 agonists, inducing cytokine production and upregulating CD40 and CD86 expressions. The TLR2/6 agonistic lipopeptides were further assessed for vaccine adjuvant effects in mice. The results confirmed that the R-stereochemistry at the thio-glycerol lipopeptide core was preferred for maximal TLR2/6 activity, as reflected in Th1 immune deviation, higher antibody levels and enhanced vaccine protection against a lethal influenza challenge.

| S-EPMC9132229 | biostudies-literature

Facile and Scalable Synthesis of Metal- and Nitrogen-Doped Carbon Nanotubes for Efficient Electrochemical CO2 Reduction.

Project description:Metal- and nitrogen-doped carbon (M-N-C) is a promising material to catalyze electrochemical CO2 reduction reaction (CO2RR). However, most M-N-C catalysts in the literature require complicated synthesis procedures and produce small quantities per batch, limiting the commercialization potential. In this work, we developed a simple and scalable synthesis method to convert metal-impurity-containing commercial carbon nanotubes (CNTs) and nitrogen-containing organic precursors into M-N-C via one-step moderate-temperature (650 °C) pyrolysis without any other treatment nor the need to add metal precursors. Batches of catalysts in varied mass up to 10 g (150 mL in volume) per batch were synthesized, and repeatable catalytic performances were demonstrated. To the best of our knowledge, the 10 g batch is one of the largest batches of CO2RR catalysts synthesized in the literature while requiring minimal synthesis steps. The catalyst possessed single-atomic iron-nitrogen (Fe-N) sites, enabling a high performance of >95% CO product selectivity at a high current density of 400 mA/cm2 and high stability for 45 h at 100 mA/cm2 in a flow cell testing. The catalyst outperformed a benchmark noble-metal nanoparticle catalyst and achieved longer stability than many other reported M-N-C catalysts in the literature. The scalable and cost-effective synthesis developed in this work paves a pathway toward practical CO2RR applications. The direct utilization of metal impurities from raw CNTs for efficient catalyst synthesis with minimal treatment is a green and sustainable engineering approach.

| S-EPMC10853974 | biostudies-literature

Overcoming antibiotic resistance through efficient and scalable total synthesis.

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| S-EPMC9744093 | biostudies-literature

Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation.

Project description:Toll-like receptor 2 (TLR2) responses are involved in various inflammatory immune disorders. Phloretin is a naturally occurring dietary flavonoid that is abundant in fruit. Here, we investigated whether the anti-inflammatory activity of phloretin is mediated through TLR2 pathways, and whether phloretin acts as an inhibitor of TLR2/1 heterodimerization using the TLR2/1 agonist Pam₃CSK₄. We tested the effects of phloretin on tumor necrosis factor (TNF)-α production induced by various TLRs using known TLR-specific agonists. Phloretin significantly inhibited Pam₃CSK₄-induced TRL2/1 signaling in Raw264.7 cells compared to TLR signaling induced by the other agonists tested. Therefore, we further tested the effects of phloretin in human embryonic kidney (HEK) 293-hTLR2 cells induced by Pam₃CSK₄, and confirmed that phloretin has comparable inhibition of TLR2/1 heterodimerization to that induced by the known TLR2 inhibitor CU-CPT22. Moreover, phloretin reduced the secretion of the inflammatory cytokines TNF-α and interleukin (IL)-8 in Pam₃CSK₄-induced HEK293-hTLR2 cells, whereas it did not significantly reduce these cytokines under Pam₂CSK₄-induced activation. Western blot results showed that phloretin significantly suppressed Pam₃CSK₄-induced TLR2 and NF-κB p65 expression. The molecular interactions between phloretin and TLR2 were investigated using bio-layer interferometry and in silico docking. Phloretin bound to TLR2 with micromolar binding affinity, and we proposed a binding model of phloretin at the TLR2⁻TLR1 interface. Overall, we confirmed that phloretin inhibits the heterodimerization of TLR2/1, highlighting TLR2 signaling as a therapeutic target for treating TLR2-mediated inflammatory immune diseases.

| S-EPMC6073418 | biostudies-literature

Potent adjuvantic activity of a CCR1-agonistic bis-quinoline.

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| S-EPMC3248955 | biostudies-literature

Potent adjuvanticity of a pure TLR7-agonistic imidazoquinoline dendrimer.

Project description:Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen.

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The Scalable Solid-State Synthesis of a Ni5P4/Ni2P-FeNi Alloy Encapsulated into a Hierarchical Porous Carbon Framework for Efficient Oxygen Evolution Reactions.

Project description:The exploration of high-performance and low-cost electrocatalysts towards the oxygen evolution reaction (OER) is essential for large-scale water/seawater splitting. Herein, we develop a strategy involving the in situ generation of a template and pore-former to encapsulate a Ni5P4/Ni2P heterojunction and dispersive FeNi alloy hybrid particles into a three-dimensional hierarchical porous graphitic carbon framework (labeled as Ni5P4/Ni2P-FeNi@C) via a room-temperature solid-state grinding and sodium-carbonate-assisted pyrolysis method. The synergistic effect of the components and the architecture provides a large surface area with a sufficient number of active sites and a hierarchical porous pathway for efficient electron transfer and mass diffusion. Furthermore, a graphitic carbon coating layer restrains the corrosion of alloy particles to boost the long-term durability of the catalyst. Consequently, the Ni5P4/Ni2P-FeNi@C catalyst exhibits extraordinary OER activity with a low overpotential of 242 mV (10 mA cm-2), outperforming the commercial RuO2 catalyst in 1 M KOH. Meanwhile, a scale-up of the Ni5P4/Ni2P-FeNi@C catalyst created by a ball-milling method displays a similar level of activity to the above grinding method. In 1 M KOH + seawater electrolyte, Ni5P4/Ni2P-FeNi@C also displays excellent stability; it can continuously operate for 160 h with a negligible potential increase of 2 mV. This work may provide a new avenue for facile mass production of an efficient electrocatalyst for water/seawater splitting and diverse other applications.

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Facile and Scalable Synthesis of Robust Ni(OH)2 Nanoplate Arrays on NiAl Foil as Hierarchical Active Scaffold for Highly Efficient Overall Water Splitting.

Project description:Developing highly efficient low-cost electrocatalysts for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in alkaline electrolyte is essential to advance water electrolysis technology. Herein, Ni(OH)2 nanoplates aligned on NiAl foil (Ni(OH)2/NiAl) are developed by simply dealloying NiAl foil in KOH, which exhibits high electrocatalytic activity for OER with a small overpotential of 289 mV to achieve 10 mA cm-2 and outstanding durability with no detectable degradation during long-term operation. Furthermore, such Ni(OH)2/NiAl can effectively act as an active and robust hierarchical scaffold to simply electrodeposit other catalysts with intrinsically higher activity such as NiMo and NiFe nanoparticles for highly efficient HER and OER, respectively. The prepared NiFe/Ni(OH)2/NiAl displays superior OER catalytic activity with overpotentials of 246, 315, and 374 mV at 10, 100, and 500 mA cm-2, respectively. While NiMo/Ni(OH)2/NiAl catalyst exhibits remarkable HER performance with a small overpotential of 78 mV to deliver 10 mA cm-2. Consequently, the electrolysis device composed of the above two electrocatalysts demonstrates superb water splitting performance with a cell voltage of 1.59 V at 10 mA cm-2. These results open up opportunities to explore and optimize low-cost advanced catalysts for energy applications.

| S-EPMC5566344 | biostudies-literature

Scalable Synthesis of Biodegradable Black Mesoporous Silicon Nanoparticles for Highly Efficient Photothermal Therapy.

Project description:Porous silicon (PSi) has attracted wide interest as a potential material for various fields of nanomedicine. However, until now, the application of PSi in photothermal therapy has not been successful due to its low photothermal conversion efficiency. In the present study, biodegradable black PSi (BPSi) nanoparticles were designed and prepared via a high-yield and simple reaction. The PSi nanoparticles possessed a low band gap of 1.34 eV, a high extinction coefficient of 13.2 L/g/cm at 808 nm, a high photothermal conversion efficiency of 33.6%, good photostability, and a large surface area. The nanoparticles had not only excellent photothermal properties surpassing most of the present inorganic photothermal conversion agents (PCAs) but they also displayed good biodegradability, a common problem encountered with the inorganic PCAs. The functionality of the BPSi nanoparticles in photothermal therapy was verified in tumor-bearing mice in vivo. These results showed clearly that the photothermal treatment was highly efficient to inhibit tumor growth. The designed PCA material of BPSi is robust, easy to prepare, biocompatible, and therapeutically extremely efficient and it can be integrated with several other functionalities on the basis of simple silicon chemistry.

| S-EPMC6150643 | biostudies-literature