Class Of Ligands Research Articles

Asking Ligands to Lend a Hand

In classical transition-metal-catalysts, the ligand is a spectator, while all key transformations such as oxidative addition, β-hydride elimination and reductive elimination occur at the metal center. Herein, the ligand plays no direct role in the catalytic cycle and its function is limited to stabilizing the metal center and tuning its coordination environment. In recent years, participating ligands, which play an active role during the course of reaction, have received greater attention. The use of such ligands has allowed for the development of more active/selective catalysts and opened up new reaction pathways. There are many ways in which a ligand can influence the metal center to accelerate the catalytic transformation. For example, hemilabile ligands allow reversible dissociation of a donor unit to adapt to the stereoelectronic requirements of the reaction intermediates.Redox-non-innocent ligands participate in transferring electrons to/from the metal. There is a class of ligands that directly participate in bond making/breaking and undergo reversible chemical transformation during the catalytic cycle.These modes of ligand cooperativity have been discussed in many excellent reviews including those by Caulton,Milsteinand Grützmacher. Herein, we aim to address two distinct strategies to achieve ‘ligand-driven-chemistry’ – the use of (a) electronically asymmetric ligand, and (b) protic ligands. A brief discussion on the role of ligands in water activation for functionalization of organic compounds is given at the end.

Discovery of novel protein degraders based on bioorthogonal reaction-driven intracellular self-assembly strategy

Proteolysis targeting chimera (PROTAC) is a promising therapeutic modality capable of degrading undruggable proteins and overcoming the shortcomings of traditional inhibitors. However, the molecular weight and pharmaceutical properties of PROTACs fall outside of a reasonable range. To overcome the inherent poor druggability of PROTACs, an intracellular self-assembly strategy based on bio-orthogonal reaction was proposed and applied in this study. Herein, two novel classes of intracellular precursors that can self-assemble into protein degraders through bio-orthogonal reactions were explored, including a novel class of E3 ubiquitin ligase ligands bearing tetrazine (E3L-Tz) and target protein ligands incorporated with norbornene (TPL-Nb). These two types of precursors could spontaneously undergo bio-orthogonal reactions in living cells, affording novel PROTACs. Among these precursors, the biological activities of PROTACs formed by target protein ligand with norbornene group (S4N-1) were more potent than others and degrade VEGFR-2, PDGFR-β and EphB4. The results demonstrated that a highly specific bio-orthogonal reaction driven intracellular self-assembly strategy in living cells could be utilized to improve the degradation activity of PROTACs.

Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [18F]LUZ5-d8.

The development of cannabinoid receptor type 2 (CB2R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB2R radioligands, a carborane moiety was used as a bioisostere. Here we report the synthesis and characterization of carborane-based 1,8-naphthyridinones and thiazoles as novel CB2R ligands. All tested compounds showed low nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide (LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity CB2R ligands, while the in vivo pharmacology still needs to be addressed.

ABC transporters linked to multiple herbicide resistance in blackgrass (Alopecurus myosuroides).

Enhanced detoxification is a prominent mechanism protecting plants from toxic xenobiotics and endows resistance to diverse herbicide chemistries in grass weeds such as blackgrass (Alopecurus myosuroides). The roles of enzyme families which impart enhanced metabolic resistance (EMR) to herbicides through hydroxylation (phase 1 metabolism) and/or conjugation with glutathione or sugars (phase 2) have been well established. However, the functional importance of herbicide metabolite compartmentalisation into the vacuole as promoted by active transport (phase 3), has received little attention as an EMR mechanism. ATP-binding cassette (ABC) transporters are known to be important in drug detoxification in fungi and mammals. In this study, we identified three distinct C-class ABCCs transporters namely AmABCC1, AmABCC2 and AmABCC3 in populations of blackgrass exhibiting EMR and resistance to multiple herbicides. Uptake studies with monochlorobimane in root cells, showed that the EMR blackgrass had an enhanced capacity to compartmentalize fluorescent glutathione-bimane conjugated metabolites in an energy-dependent manner. Subcellular localisation analysis using transient expression of GFP-tagged AmABCC2 assays in Nicotiana demonstrated that the transporter was a membrane bound protein associated with the tonoplast. At the transcript level, as compared with herbicide sensitive plants, AmABCC1 and AmABCC2 were positively correlated with EMR in herbicide resistant blackgrass being co-expressed with AmGSTU2a, a glutathione transferase (GST) involved in herbicide detoxification linked to resistance. As the glutathione conjugates generated by GSTs are classic ligands for ABC proteins, this co-expression suggested AmGSTU2a and the two ABCC transporters delivered the coupled rapid phase 2/3 detoxification observed in EMR. A role for the transporters in resistance was further confirmed in transgenic yeast by demonstrating that the expression of either AmABCC1 or AmABCC2, promoted enhanced tolerance to the sulfonylurea herbicide, mesosulfuron-methyl. Our results link the expression of ABCC transporters to enhanced metabolic resistance in blackgrass through their ability to transport herbicides, and their metabolites, into the vacuole.

Room-Temperature Cu-Catalyzed Amination of Aryl Bromides Enabled by DFT-Guided Ligand Design.

Ullmann-type C-N coupling reactions represent an important alternative to well-established Pd-catalyzed approaches due to the differing reactivity and the lower cost of Cu. While the design of anionic Cu ligands, particularly those by Ma, has enabled the coupling of various classes of aryl halides and alkyl amines, most methods require conditions that can limit their utility on complex substrates. Herein, we disclose the development of anionic N1,N2-diarylbenzene-1,2-diamine ligands that promote the Cu-catalyzed amination of aryl bromides under mild conditions. Guided by DFT calculations, these ligands were designed to (1) increase the electron density on Cu, thereby increasing the rate of oxidative addition of aryl bromides, and (2) stabilize the active anionic CuI complex via a π-interaction. Under optimized conditions, structurally diverse aryl and heteroaryl bromides and a broad range of alkyl amine nucleophiles, including pharmaceuticals bearing multiple functional groups, were efficiently coupled at room temperature. Combined computational and experimental studies support a mechanism of C-N bond formation that follows a catalytic cycle akin to the well-explored Pd-catalyzed variants. Modification of the ligand structure to include a naphthyl residue resulted in a lower energy barrier to oxidative addition, providing a 30-fold rate increase relative to what is seen with other ligands. Collectively, these results establish a new class of anionic ligands for Cu-catalyzed C-N couplings, which we anticipate may be extended to other Cu-catalyzed C-heteroatom and C-C bond-forming reactions.

Aryl Triflates in Phosphorus-Directed Rhodium(III)-Catalyzed C–H Activation

AbstractAryl triflates are selected as suitable electrophile coupling partners for the phosphorus-directed rhodium(III)-catalyzed direct C–H arylation of polyaromatic phosphines. We report herein simple conditions for the peri-C–H functionalization of polyarylphosphines, where a [Rh(III)Cl2Cp*]2 precatalyst is employed to provide a convenient access to polyarylated phosphines in up to 93% isolated yield. This synthetic approach tolerates a wide range of different aryl trifluoromethylsulfonate derivatives bearing either electron-donating (COMe, CN, CF3 or Cl) or electron-withdrawing substituents (Me, OMe) at the para-, meta- and ortho-positions, and includes bulky polyaromatic triflate substrates. We further describe access to a large class of polycyclic aromatic hydrocarbon phosphine ligands, their oxidized derivatives (i.e., their oxides and selenides), their coordination modes with Au(I) and Cu(I) coinage metal salts, and their use as efficient ligands for the atom-economic, gold-catalyzed oxidative cyclization of terminal alkynes with nitriles.

Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency

PD-1/PD-L1 protein complex is attracting a great deal of interest as a drug target for the design of immune therapies able to block its assembly. Although some biologic drugs have entered clinical use, their poor response rate in patients are demanding further efforts to design small molecule inhibitors of PD-1/PD-L1 complex with higher efficacy and optimal physicochemical properties. Dysregulation of pH in the tumor microenvironment is indeed one of the key mechanisms promoting drug resistance and lack of response in cancer therapy. Integrating computational and biophysical approaches, herein we report a screening campaign that has led to identifying VIS310 as a novel ligand of PD-L1, with physicochemical properties enabling a pH-dependent binding potency. Additional optimization efforts by analogue-based screening have been instrumental to disclosing VIS1201, which exhibits improved binding potency against PD-L1 and is able to inhibit PD-1/PD-L1 complex formation in a ligand binding displacement assay. While providing preliminary structure-activity relationships (SARs) of a novel class of PD-L1 ligands, our results lay the foundation for the discovery of immunoregulatory small molecules resilient to tumor microenvironmental conditions for escaping drug-resistance mechanisms.

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma.

The key role of tissue-resident memory T (TRM) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on TRM cells is still unclear. Lymphocyte activating gene 3 (LAG-3) is a promising next-generation immune checkpoint that is continuously expressed due to persistent antigen exposure in the tumor microenvironment. Fibrinogen-like protein 1 (FGL1) is a classical ligand of LAG-3 and can promote T cell exhaustion in tumors. Here, we excavated the effect of FGL1-LAG3 regulatory axis on TRM cells in HCC. The function and phenotype of intrahepatic CD8+ TRM cells in 35 HCC patients were analyzed using multicolor flow cytometry. Using a tissue microarray of 80 HCC patients, we performed the prognosis analysis. Moreover, we investigated the suppressive effect of FGL1 on CD8+ TRM cells both in in vitro induction model and in vivo orthotopic HCC mouse model. There was an increase in LAG3 expression in CD8+ TRM cells in end-stage HCC; moreover, FGL1 levels were negatively correlated with CD103 expression and related to poor outcomes in HCC. Patients with high CD8+ TRM cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8+ TRM cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8+ TRM cell exhaustion, causing tumor immune escape. We identified CD8+TRM cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8+ TRM cell function in HCC.

Highly Adaptive Nature of Group 15 Tris(quinolyl) Ligands─Studies with Coinage Metals

The substitution of heavier, more metallic atoms into classical organic ligand frameworks provides an important strategy for tuning ligand properties, such as ligand bite and donor character, and is the basis for the emerging area of main-group supramolecular chemistry. In this paper, we explore two new ligands [E(2-Me-8-qy)3] [E = Sb (1), Bi (2); qy = quinolyl], allowing a fundamental comparison of their coordination behavior with classical tris(2-pyridyl) ligands of the type [E'(2-py)3] (E = a range of bridgehead atoms and groups, py = pyridyl). A range of new coordination modes to Cu+, Ag+, and Au+ is seen for 1 and 2, in the absence of steric constraints at the bridgehead and with their more remote N-donor atoms. A particular feature is the adaptive nature of these new ligands, with the ability to adjust coordination mode in response to the hard-soft character of coordinated metal ions, influenced also by the character of the bridgehead atom (Sb or Bi). These features can be seen in a comparison between [Cu2{Sb(2-Me-8-qy)3}2](PF6)2 (1·CuPF6) and [Cu{Bi(2-Me-8-qy)3}](PF6) (2·CuPF6), the first containing a dimeric cation in which 1 adopts an unprecedented intramolecular N,N,Sb-coordination mode while in the second, 2 adopts an unusual N,N,(π-)C coordination mode. In contrast, the previously reported analogous ligands [E(6-Me-2-py)3] (E = Sb, Bi; 2-py = 2-pyridyl) show a tris-chelating mode in their complexes with CuPF6, which is typical for the extensive tris(2-pyridyl) family with a range of metals. The greater polarity of the Bi-C bond in 2 results in ligand transfer reactions with Au(I). Although this reactivity is not in itself unusual, the characterization of several products by single-crystal X-ray diffraction provides snapshots of the ligand transfer reaction involved, with one of the products (the bimetallic complex [(BiCl){ClAu2(2-Me-8-qy)3}] (8)) containing a Au2Bi core in which the shortest Au → Bi donor-acceptor bond to date is observed.

Triflate vs Acetonitrile: Understanding the Iron(II)-Based Coordination Chemistry of Tri(quinolin-8-yl)amine

In this study, a synthesis route of tri(quinolin-8-yl)amine (L), a recent member of the tetradentate tris(2-pyridylmethyl)amine (TPA) ligand family, is reported. With the neutral ligand L bound to an iron(II) center in κ4 mode, two cis-oriented coordination sites remain vacant. These can be occupied by coligands such as counterions and solvent molecules. How sensitive this equilibrium can be is most evident if both triflate anions and acetonitrile molecules are available. All three combinations─bis(triflato), bis(acetonitrile), and mixed coligand species─could be characterized by single-crystal X-ray diffraction (SCXRD), which is unique so far for this class of ligand. While at room temperature, the three compounds tend to crystallize concomitantly, the equilibrium can be shifted in favor of the bis(acetonitrile) species by lowering the crystallization temperature. Removed from their mother liquor, the latter is very sensitive to evaporation of the residual solvent, which was observed by powder X-ray diffraction (PXRD) and Mössbauer spectroscopy. The solution behavior of the triflate and acetonitrile species was studied in detail using time- and temperature-resolved UV/vis spectroscopy, Mössbauer spectroscopy of frozen solution, NMR spectroscopy, and magnetic susceptibility measurements. The results indicate a bis(acetonitrile) species in acetonitrile showing a temperature-dependent spin-switching behavior between high- and low-spin. In dichloromethane, the results reveal a high-spin bis(triflato) species. In pursuit of understanding the coordination environment equilibria of the [Fe(L)]2+ complex, a series of compounds with different coligands was prepared and analyzed with SCXRD. The crystal structures indicate that the spin state can be controlled by changing the coordination environment─all of the {N6}-coordinated complexes display geometries expected for low-spin species, while any other donor atom in the coligand position induces a shift to the high-spin state. This fundamental study sheds light on the coligand competition of triflate and acetonitrile, and the high number of crystal structures allows further insights into the influence of different coligands on the geometry and spin state of the complexes.

Counterintuitive Chemistry: Carbene Stabilization of Zero-Oxidation State Main Group Species

Carbenes have evolved from transient laboratory curiosities to a robust, diverse, and surprisingly impactful ligand class. A variety of different carbenes have significantly contributed to the development of low-oxidation state main group chemistry. This Perspective focuses upon advances in the chemistry of carbene complexes containing main group element cores in the formal oxidation state of zero, including their diverse synthetic strategies, unusual bonding and structural motifs, and utility in transition metal coordination chemistry and activation of small molecules.

Solid Phase Synthesis of Fluorosulfate Containing Macrocycles for Chemoproteomic Workflows

AbstractMacrocyclic peptides are attractive for chemoproteomic applications due to their modular synthesis and potential for high target selectivity. We describe a solid phase synthesis method for the efficient generation of libraries of small macrocycles that contain an electrophile and alkyne handle. The modular synthesis produces libraries that can be directly screened using simple SDS‐PAGE readouts and then optimal lead molecules applied to proteomic analysis. We generated a library of 480 macrocyclic peptides containing the weakly reactive fluorosulfate (OSF) electrophile. Initial screening of a subset of the library containing each of the various diversity elements identified initial molecules of interest. The corresponding positional and confirmational isomers were then screened to select molecules that showed specific protein labeling patterns that were dependent on the probe structure. The most promising hits were applied to standard chemoproteomic workflows to identify protein targets. Our results demonstrate the feasibility of rapid, on‐resin synthesis of diverse macrocyclic electrophiles to generate new classes of covalent ligands.

Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations.

Protein kinase C delta (PKC-δ) is an important signaling molecule in human cells that has both proapoptotic as well as antiapoptotic functions. These conflicting activities can be modulated by two classes of ligands, phorbol esters and bryostatins. Phorbol esters are known tumor promoters, while bryostatins have anti-cancer properties. This is despite both ligands binding to the C1b domain of PKC-δ (δC1b) with a similar affinity. The molecular mechanism behind this discrepancy in cellular effects remains unknown. Here, we have used molecular dynamics simulations to investigate the structure and intermolecular interactions of these ligands bound to δC1b with heterogeneous membranes. We observed clear interactions between the δC1b-phorbol complex and membrane cholesterol, primarily through the backbone amide of L250 and through the K256 side-chain amine. In contrast, the δC1b-bryostatin complex did not exhibit interactions with cholesterol. Topological maps of the membrane insertion depth of the δC1b-ligand complexes suggest that insertion depth can modulate δC1b interactions with cholesterol. The lack of cholesterol interactions suggests that bryostatin-bound δC1b may not readily translocate to cholesterol-rich domains within the plasma membrane, which could significantly alter the substrate specificity of PKC-δ compared to δC1b-phorbol complexes.

Introducing Conformational Restraints on 25CN-NBOH: A Selective 5-HT2A Receptor Agonist.

The N-benzylphenethylamines (NBOMes) are a class of ligands from which compounds with impressive selectivity for the serotonin 2A receptor (5-HT2AR) over the closely related serotonin 2C receptor (5-HT2CR) have emerged. These include 4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile (25CN-NBOH, 1) and 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine (DMPMBB, 2). The present work entails the synthesis and characterization of ligands wherein the structures of these two molecules have been fused. The desired compounds were accessed by a six-step synthetic procedure followed by the chiral resolution of the resulting racemic mixtures, giving one active ((S,S)-3) and three essentially inactive stereoisomers. In silico experiments support that one of the four possible stereoisomers would be active. Further in silico investigations showed that 1, 2, and (S,S)-3 share a common binding mode, further supporting the shared stereochemistry between the active enantiomer ((S,S)-3) and 2.

Chiral Dienes: A Unique Class of Ligands in Asymmetric Catalysis.

Chiral Dienes: A Unique Class of Ligands in Asymmetric Catalysis.

Development of Substituted Phenyl Dihydrouracil as the Novel Achiral Cereblon Ligands for Targeted Protein Degradation.

Glutarimides such as thalidomide, pomalidomide, and lenalidomide are the most frequently used ligands to recruit E3 ubiquitin ligase cereblon (CRBN) for the development of proteolysis-targeting chimeras (PROTACs). Due to the rapid and spontaneous racemization of glutarimides, most CRBN-recruiting PROTACs are synthesized as a mixture of racemates or diastereomers. Since the (S)-enantiomer is primarily responsible for binding to CRBN, the existence of the largely inactive (R)-enantiomer complicates the drug development process. Herein, we report that substituted achiral phenyl dihydrouracil (PDHU) can be used as a novel class of CRBN ligands for the development of PROTACs. Although the parent PDHU has a minimal binding affinity to CRBN, we found that some substituted PDHUs had a comparable binding affinity to lenalidomide. Structural modeling provided a further understanding of the molecular interactions between PDHU ligands and CRBN. PDHUs also have greater stability than lenalidomide. Finally, potent BRD4 degraders were developed by employing trisubstituted PDHUs.

Endocannabinoid Degradation Enzyme Inhibitors as Potential Antipsychotics: A Medicinal Chemistry Perspective

The endocannabinoid system (ECS) plays a very important role in numerous physiological and pharmacological processes, such as those related to the central nervous system (CNS), including learning, memory, emotional processing, as well pain control, inflammatory and immune response, and as a biomarker in certain psychiatric disorders. Unfortunately, the half-life of the natural ligands responsible for these effects is very short. This perspective describes the potential role of the inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), which are mainly responsible for the degradation of endogenous ligands in psychic disorders and related pathologies. The examination was carried out considering both the impact that the classical exogenous ligands such as Δ9-tetrahydrocannabinol (THC) and (-)-trans-cannabidiol (CBD) have on the ECS and through an analysis focused on the possibility of predicting the potential toxicity of the inhibitors before they are subjected to clinical studies. In particular, cardiotoxicity (hERG liability), probably the worst early adverse reaction studied during clinical studies focused on acute toxicity, was predicted, and some of the most used and robust metrics available were considered to select which of the analyzed compounds could be repositioned as possible oral antipsychotics.

The piperazine analogue para-fluorophenylpiperazine alters timing of the physiological effects of the synthetic cannabinoid receptor agonist AMB-FUBINACA, without changing its discriminative stimulus, signalling effects, or metabolism

AMB-FUBINACA is a synthetic cannabinoid receptor agonist (SCRA), which has been associated with substantial abuse and health harm since 2016 in many countries including New Zealand. A characteristic of AMB-FUBINACA use in New Zealand has included the observation that forensic samples (from autopsies) and drugs seized by police have often been found to contain para-fluorophenylpiperazine (pFPP), a relatively little-characterised piperazine analogue that has been suggested to act through 5HT1a serotonin receptors. In the current study, we aimed to characterise the interactions of these two agents in rat physiological endpoints using plethysmography and telemetry, and to examine whether pFPP altered the subjective effects of AMB-FUBINACA in mice trained to differentiate a cannabinoid (THC) from vehicle. Though pFPP did not alter the ability of AMB-FUBINACA to substitute for THC, it did appear to abate some of the physiological effects of AMB-FUBINACA in rats by delaying the onset of AMB-FUBINACA-mediated hypothermia and shortening duration of bradycardia. In HEK cells stably expressing the CB1 cannabinoid receptor, 5HT1a, or both CB1 and 5HT1a, cAMP signalling was recorded using a BRET biosensor (CAMYEL) to assess possible direct receptor interactions. Although low potency pFPP agonism at 5HT1a was confirmed, little evidence for signalling interactions was detected in these assays: additive or synergistic effects on potency or efficacy were not detected between pFPP and AMB-FUBINACA-mediated cAMP inhibition. Experiments utilising higher potency, classical 5HT1a ligands (agonist 8OH-DPAT and antagonist WAY100635) also failed to reveal evidence for mutual CB1/5HT1a interactions or cross-antagonism. Finally, the ability of pFPP to alter the metabolism of AMB-FUBINACA in rat and human liver microsomes into its primary carboxylic acid metabolite via carboxylesterase-1 was assessed by HPLC; no inhibition was detected. Overall, the effects we have observed do not suggest that increased harm/toxicity would result from the combination of pFPP and AMB-FUBINACA.

Pincer Platinum(II) Hydrides: High Stability Imparted by Donor-Flexible Pyridylidene Amide Ligands and Evidence for Adduct Formation before Protonation

Donor-flexible ligands are an emerging class of noninnocent ligands. Their ability to adapt their donating strength toward a metal center has had numerous catalytic advantages yet has never been utilized to stabilize and isolate intermediate complexes within these processes. We demonstrate through the use of a pincer ligand containing two donor-flexible pyridylidene amide (PYA) arms in coordination with platinum(II) that this ligand adaptability revealed remarkably stable hydride and formate complexes. These are typically fleeting catalytic intermediates within formic acid dehydrogenation and CO2 hydrogenation catalytic cycles. The PYA platinum hydride complexes are indefinitely stable in air, while formate complexes show no sign of β-hydrogen elimination. This robustness allowed us to investigate hydride protonation as a seemingly simple reaction, though in-depth kinetic analysis reveals a pre-equilibrium step prior to platinum hydride protonation. This initial step has been attributed to adduct formation and is slower than the protonation, and therefore a relevant aspect when designing catalytic cycles for hydrogen release and its microscopic reverse, viz., hydrogen uptake.

P021 Microbial metabolite receptors as mediators of pathogenic processes in Inflammatory Bowel Disease.

Abstract Background Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition of the alimentary tract, primarily manifested as Crohn’s disease and Ulcerative colitis. Dysbiosis of the intestinal microbial microflora is a well-established characteristic of IBD. The microbiota metabolism ends in the production of several metabolites that participate in interactions with the host and ultimately influence its physiology. Our aim is to investigate whether metabolite receptor expression differs between IBD and healthy individuals and unravel their possible interactions with inflammatory and fibrotic pathways in the intestine. Methods RNA-sequencing data from over 2500 intestinal biopsy samples were collected from publicly available datasets via the Sequence Read Archive. Bioinformatics analysis of metabolite receptor genes was performed using the RaNA-seq online platform which included normalization, alignment and differential expression. In addition, correlation analysis between the target receptor genes and inflammatory/fibrotic genes as well as functional analysis was performed via a R based pipeline to elucidate molecular interactions during IBD. Results The expression of 22 receptors responding to the major metabolite ligand classes bile acids, short chain fatty acids and indole derivatives from tryptophan metabolism was targeted. Several receptors of bile acids as well as receptors of short chain fatty acids, such as the vitamin D receptor (VDR), the peroxisome proliferator-activated receptor alpha (PPARα) and the hydroxycarboxylic acid receptor 2 (HCAR2), were found differentially expressed in intestinal biopsies of CD patients as compared to healthy individuals. Negative and positive correlation of these receptors with genes of known involvement in IBD was explored, along with their simultaneous contributions to inflammatory and fibrotic processes. Conclusion Our results demonstrate the interplay between the intestinal microbiota and the host on a metabolite-receptor level and identify disease related interactions with inflammation and fibrosis.