P139 Effect of Lysosomal Short Chain Fatty Acid Delivery on Immune Response

Straß, Simon; Heinzel, Constanze; Cloos, Natascha; Keppler, Manuel; Guse, Jan; Burnet, Michael; Laufer, Stefan

doi:10.1053/j.gastro.2019.11.082

Cited by 2 publications

(5 citation statements)

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“…Pharmacokinetics were investigated in mice to determine the distribution and metabolism of 1 a and 2 a . One area of intended application of the substances is IBD where the lysosomal delivery of SCFAs should stimulate both gut epithelium and associated lamina propria immune cells [22,55] . This use implies that oral administration should provide availability in the intestine and that the drugs should be metabolized there to provide tissue with the desired SCFAs.…”

Section: Resultsmentioning

confidence: 99%

“…Esters are well known to hydrolyze chemically, or via esterases or lipases, and our earlier work had demonstrated the lability of the 2' esters. [22,23] To ensure that the compounds could be prepared and stored in a stable form we investigated their stability in solution under various conditions and to support analysis of possible pharmacokinetic studies. In particular, the 2' position of Azithromycin interacts with the bacterial ribosome.…”

Section: Stability Studiesmentioning

confidence: 99%

“…The substances we describe here are active in the range of 0.1 mg/kg and are thus much more efficient than free SCFAs. [22,23] Sensing of SCFAs appears to take place at several levels. Colonocytes have surface receptors which appear to regulate tight junction formation and density.…”

Section: Introductionmentioning

confidence: 99%

“…While the technology for widespread therapy with microorganisms is developing, a simplified small molecule approach that simulates a healthy microbiome may be one means to use knowledge and to mimic the microbiome in the treatment of gut disorders. The substances we describe here are active in the range of 0.1 mg/kg and are thus much more efficient than free SCFAs [22,23] …”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and in vivo Distribution of Intracellular Delivered Macrolide Short‐Chain Fatty Acid Derivatives

et al. 2021

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Short-chain fatty acids (SCFAs) have a range of effects in metabolism and immune regulation. We have observed that delivery of SCFAs to lysosomes has potent immune regulatory effects, possibly as a surrogate signal for the presence of anaerobic organisms. To better understand the pharmacology of lysosomal SCFA donors, we investigated the distribution and metabolism of propionate and butyrate donors. Each analog (1 a and 2 a) can donate three SCFA equivalents via ester hydrolysis through six intermediate metabolites. The compounds are stabilized by low pH, and stability in cells is usually higher than in medium, but is cell-type specific. Butyrate derivatives were found to be more stable than propionates. Triesters were more stable than di-or mono-esters. The donors were surprisingly stable in vivo, and hydrolysis of each position was organ specific. Jejunum and liver caused rapid loss of 4'' esters. The gut metabolite pattern by i. v. differed from that of p.o. application, suggesting luminal and apical enzyme effects in the gut epithelium. Central organs could de-esterify the 11position. Levels in lung relative to other organs were higher by p.o. than via i. v., suggesting that delivery route can influence the observed pharmacology and that gut metabolites distribute differently. The donors were largely eliminated by 24 h, following near linear decline in organs. The observed levels and distribution were found to be consistent with pharmacodynamic effects, particularly in the gut.

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Section: Resultsmentioning

confidence: 99%

Section: Stability Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and in vivo Distribution of Intracellular Delivered Macrolide Short‐Chain Fatty Acid Derivatives

et al. 2021

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“…Building on our previous experience with macrolide-derivatives (53,61), we aimed to prepare TLR7/8 ligands with high exposure to the endo/lysosomal lumen by exploiting the properties of acid trapping in the assumption that amphiphiles would be ideal ligands for endosomal TLRs. Since endosomal tropism has been observed for both macrolides as well as imidazoquinolines, we propose that conjugation of imidazoquinoline TLR7/8 agonists to Azithromycin as a carrier molecule is likely to result in conjugates that accumulate intracellularly as well.…”

Section: Introductionmentioning

confidence: 99%

Imidazoquinolines with improved pharmacokinetic properties induce a high IFNα to TNFα ratio in vitro and in vivo

et al. 2023

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TLR Agonists have promising activity in preclinical models of viral infection and cancer. However, clinical use is only in topical application. Systemic uses of TLR-ligands such as Resiquimod, have failed due to adverse effects that limited dose and thus, efficacy. This issue could be related to pharmacokinetic properties that include fast elimination leading to low AUC with simultaneously high cmax at relevant doses. The high cmax is associated with a sharp, poorly tolerated cytokine pulse, suggesting that a compound with a higher AUC/cmax-ratio could provide a more sustained and tolerable immune activation. Our approach was to design TLR7/8-agonist Imidazoquinolines intended to partition to endosomes via acid trapping using a macrolide-carrier. This can potentially extend pharmacokinetics and simultaneously direct the compounds to the target compartment. The compounds have hTLR7/8-agonist activity (EC50 of the most active compound in cellular assays: 75-120 nM hTLR7, 2.8-3.1 µM hTLR8) and maximal hTLR7 activation between 40 and 80% of Resiquimod. The lead candidates induce secretion of IFNα from human Leukocytes in the same range as Resiquimod but induce at least 10-fold less TNFα in this system, consistent with a higher specificity for human TLR7. This pattern was reproduced in vivo in a murine system, where small molecules are thought not to activate TLR8. We found that Imidazoquinolines conjugated to a macrolide or, substances carrying an unlinked terminal secondary amine, had longer exposure compared with Resiquimod. The kinetics of pro-inflammatory cytokine release for these substances in vivo were slower and more extended (for comparable AUCs, approximately half-maximal plasma concentrations). Maximal IFNα plasma levels were reached 4 h post application. Resiquimod-treated groups had by then returned to baseline from a peak at 1 h. We propose that the characteristic cytokine profile is likely a consequence of altered pharmacokinetics and, potentially, enhanced endosomal tropism of the novel substances. In particular, our substances are designed to partition to cellular compartments where the target receptor and a distinct combination of signaling molecules relevant to IFNα-release are located. These properties could address the tolerability issues of TLR7/8 ligands and provide insight into approaches to fine-tune the outcomes of TLR7/8 activation by small molecules.

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P139 Effect of Lysosomal Short Chain Fatty Acid Delivery on Immune Response

Cited by 2 publications

References 0 publications

Synthesis, Characterization, and in vivo Distribution of Intracellular Delivered Macrolide Short‐Chain Fatty Acid Derivatives

Synthesis, Characterization, and in vivo Distribution of Intracellular Delivered Macrolide Short‐Chain Fatty Acid Derivatives

Imidazoquinolines with improved pharmacokinetic properties induce a high IFNα to TNFα ratio in vitro and in vivo

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