Biology subjects

Ortlund, E. A.

Publications and source records attributed to Ortlund, E. A..

At least 19 recordsLinked to original sources

bioRxiv2026

An LRH-1 agonist reverses hepatic metabolic dysfunction in obesity

Liver receptor homolog-1 (LRH-1; NR5A2) is a nuclear receptor that controls metabolic gene programs important for liver health. Here, we address two challenges with dissecting ligand-driven LRH-1 metabolism in vivo. First, we generate ME610, a potent LRH-1 agonist with favorable pharmacokinetic properties. Second, we engineer Nr5a2humLBD mice, edited to recapitulate the ligand response of the human receptor. ME610 dose-dependently induces LRH-1 target genes and reduces triglycerides in livers of Nr5a2humLBD mice. In a mouse model of diet-induced obesity (DIO), ME610 dramatically improves insulin sensitivity and reduces liver fat. Multi-omics integration of transcriptomics, lipidomics, and metabolomics data demonstrates a coordinated reversal of DIO-induced hepatic metabolic stress via changes in lipid, amino acid, and energy metabolism, with peroxisomal lipid metabolism emerging as a central process correlated to efficacy. These studies uncover new pathways through which LRH-1 regulates metabolism and demonstrate the therapeutic potential of synthetic LRH-1 agonists in obesity-associated metabolic diseases.

physiology↗

bioRxiv2025

Temporal Multi-Omic Analysis Uncovers Sex-Biased Molecular Programs Underlying Skeletal Muscle Adaptation to Endurance Training

BackgroundExercise training is known to benefit health and reduce disease risk. While skeletal muscle adaptations are fundamental to many of the health benefits of exercise training, the common and sex-specific molecular regulators that mediate these adaptations remain to be fully elucidated. MethodsTo this end, we leveraged skeletal muscle multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), where 6 month-old male and female rats endurance trained for 1, 2, 4, or 8 weeks. Our objective was to identify shared and sex-specific multi-omic molecular responses to endurance training in skeletal muscle, and relate them to phenotypic adaptations. ResultsWe identified largely sexually-conserved transcriptomic and proteomic pathway enrichments in the gastrocnemius, which correlated with skeletal muscle responses from a published exercise study in humans. We uncovered sex-consistent post-translational modifications, including decreased oxidation of MYH2 and deacetylation of the {beta}-oxidation enzyme HADHA. Pathway enrichment analyses revealed sex-specific remodeling across the acetylome, redox proteome, and phosphoproteome; females decreased mitochondrial protein cysteine oxidation and increased mitochondrial cristae proteins, indicative of enhanced redox buffering and mitochondrial efficiency. Despite decreases in cysteine oxidation of key mitochondrial proteins, females displayed increases in the cysteine oxidation of proteins involved in glucose catabolism relative to males after 8 weeks of training, suggestive of sex-biased subcellular reactive oxygen species generation. Males demonstrated earlier induction of mitochondrial transcripts and predicted activation of mTOR. Although the increase in mitochondrial protein abundance was more modest in males, there was greater oxidation of mitochondrial proteins in response to training compared to females. ConclusionsThis work shows a large portion of the adaptive response to endurance training in skeletal muscle is shared between females and males, while there are distinct and nuanced sex-specific adaptations that are evident, particularly at the level of post-translational regulation.

physiology↗

bioRxiv2025

Endurance exercise drives temporal and sexual dimorphic multi-omic adaptations in liver metabolism-Findings from MoTrPAC.

The mechanisms by which exercise modulate liver metabolism, a central regulator of systemic metabolism, are poorly understood. Leveraging data from MoTrPAC, we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omic approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) complexes (at the protein level), while male livers showed an increase in acetylation of OXPHOS, TCA cycle, and fatty acid oxidation enzymes. Exercise also enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Moreover, 8 weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

physiology↗

bioRxiv2025

Sexually distinct multi omic responses to progressive endurance exercise training in the rat lung. Findings from MoTrPAC

Despite the lungs being essential for ventilation and aerobic exercise capacity, conventionally the lungs are not thought to adapt to exercise training. Endurance exercise is key to pulmonary rehabilitation programs, which also displays sex-specific differences in therapeutic efficacy. Given the molecular underpinnings of sex-specific lung adaptations to endurance exercise are uncharacterized, we used a multi-omics approach to study sex differences in the lungs of 6-month-old Fischer 344 rats in response to an 8 week progressive endurance treadmill training protocol. This was accomplished by reannotating publicly accessible data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC) and integrating newly-analyzed acetylome data to assess multi-omic sex differences in sedentary and progressively trained states. Female rats displayed enrichment in immune-related features and pathways at the transcriptome and proteome level that were maintained with training. Conversely, in the male rat lung there was an overall decrease in immune pathways following 8 weeks of training. Sexually conserved responses to training included increased enrichment in transcriptomic pathways related to type I alveoli and proteomic pathways related to cilia, and decreased mitochondrial protein acetylation. In both sexes, features known to be enriched in lung diseases were attenuated with training. Together our findings provide novel insight into sex specific responses to endurance exercise training in the rat lung and may offer translational insight into sex-specific differences in lung disease pathogenesis and treatment.

physiology↗

bioRxiv2025

Mapping affinity and allostery in human IgG antibody Fc region-Fc γ receptor interactions

IgG antibodies, required for a functional immune system, recognize antigens and neutralize pathogens using their Fab regions, while signaling to the immune system by binding to host Fc {gamma} receptors (Fc{gamma}Rs) through their Fc regions. These Fc{gamma}R interactions initiate and modulate antibody-mediated effector functions that are essential for host immunity, therapeutic monoclonal antibody effectiveness and IgG-mediated pathologies. Fc{gamma}Rs include both activating and inhibitory receptors and the relative binding affinities of the IgG Fc region to Fc{gamma}Rs that generate opposing signals is a key determinant of the immune response. Substantial research effort has been devoted to understanding and manipulating Fc{gamma}R interactions to decipher their fundamental biological activities and to develop therapeutic monoclonal antibodies with tailored effector functions. However, a common Fc-Fc{gamma}R binding interface, the high sequence identity of Fc{gamma}Rs, and the inherent conformational dynamics of the IgG Fc region, have prohibited a full understanding of these interactions, even when employing state-of-the-art biophysical and biological methods. Here, we used site-saturation libraries of the human IgG1 Fc region to determine the effective affinities of more than 98% of all possible single-site amino acid substitutions in the Fc to all human Fc{gamma}Rs, as well as the most common Fc{gamma}R polymorphisms. We provide a comprehensive analysis of Fc amino acid variations that determine Fc stability, orthosteric control of Fc{gamma}R binding, and short- and long-range allosteric control of Fc{gamma}R binding. We also predict the relative activating versus inhibitory effector function capacity of nearly every possible single-site Fc mutation.

biochemistry↗

bioRxiv2025

Translating the Post-Mortem Brain Multi-Omics Molecular Taxonomy of Alzheimer's Dementia to Living Humans

Alzheimers disease (AD) dementia is characterized by significant molecular and phenotypic heterogeneity, which confounds its mechanistic understanding, diagnosis, and effective treatment. In this study, we harness the most comprehensive dataset of paired ante-mortem blood omics, clinical, psychological, and post-mortem brain multi-omics data and neuroimaging to extensively characterize and translate the molecular taxonomy of AD dementia to living individuals. First, utilizing a comprehensive integration of eight complementary molecular layers from brain multi-omics data (N = 1,189), we identified three distinct molecular AD dementia subtypes exhibiting strong associations with cognitive decline, sex, psychological traits, brain morphology, and characterized by specific cellular and molecular drivers involving immune, vascular, and oligodendrocyte precursor cells. Next, in a significant translational effort, we developed predictive models to convert these advanced brain-derived molecular profiles (AD dementia pseudotimes and subtypes) into blood-, MRI- and psychological traits-based markers. The translation results underscore both the promise of these models and the opportunities for further enhancement. Our findings enhance the understanding of AD heterogeneity, underscore the value of multi-scale molecular approaches for elucidating causal mechanisms, and lay the groundwork for the development of novel therapies in living persons that target multi-level brain molecular subtypes of AD dementia.

neuroscience↗

bioRxiv2024

Structural basis of SARS-Cov-2 spike recognition by engineered synthetic multivalent VHH antibodies

High-throughput technologies such as next-generation sequencing (NGS), microarray-based gene synthesis, and phage display have empowered the discovery and engineering of precisely defined, synthetic antibodies with high avidity and drug-like features. Here, we describe a scalable process for engineering homo- and hetero-hexavalent variable domains of camelid heavy-chain (VHH)-Fc antibodies against the severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein. Overall, we demonstrate that VHH trimerization is an effective and modular approach for increasing the affinity of anti-S1 VHH-Fc antibodies for the highly mutated S proteins of SARS-CoV-2 variants. We show that one specific nanobody (named TB201-1) binds spike trimer protein at the interface of two neighboring RBDs, recognizing one distinct epitope on one RBD but making a set of secondary interactions with the neighboring RBD. From this structure, we determine the epitope-paratope residues responsible for spike-nanobody interaction and how mutations found in the SARS-CoV-2 variants contribute to oblate TB201-1 binding. This approach could be leveraged to improve existing antibody-based diagnostics and therapeutics targeting SARS-CoV-2 as the virus evolves.

bioengineering↗

bioRxiv2024

Design and immunogenicity of an HIV-1 clade C pediatric envelope glycoprotein stabilized by multiple platforms

Various design platforms are available to stabilize soluble HIV-1 envelope (Env) trimers, which can be used as antigenic baits and vaccine antigens. However, stabilizing HIV-1 clade C trimers can be challenging. Here, we stabilized an HIV-1 clade C trimer based on an Env isolated from a pediatric elite-neutralizer (AIIMS_329) using multiple platforms, including SOSIP.v8.2, ferritin nanoparticles (NP) and an I53-50 two-component NP, followed by characterization of their biophysical, antigenic, and immunogenic properties. The stabilized 329 Envs showed binding affinity to trimer-specific HIV-1 broadly neutralizing antibodies (bnAbs), with negligible binding to non-neutralizing antibodies (non-nAbs). Negative-stain electron microscopy (nsEM) confirmed the native-like conformation of the Envs. Multimerization of 329 SOSIP.v8.2 on ferritin and two-component I53-50 NPs improved the overall affinity to HIV-1 bnAbs and immunogenicity in rabbits. These stabilized HIV-1 clade C 329 Envs demonstrate the potential to be used as antigenic baits and as components of multivalent vaccine candidates in future.

immunology↗

bioRxiv2023

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.

molecular biology↗

bioRxiv2022

Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.

immunology↗

bioRxiv2022

High-throughput screening identifies small molecule inhibitors of thioesterase superfamily member 1: Implications for the management of non-alcoholic fatty liver disease

Thioesterase superfamily member 1 (Them1; synonyms Acyl-CoA thioesterase 11 (Acot11) and steroidogenic acute regulatory protein-related lipid transfer (START) domain 14 (StarD14) is a long chain acyl-CoA thioesterase comprising two N-terminal hot-dog fold enzymatic domains linked to a C-terminal lipid-sensing START domain, which allosterically modulates enzymatic activity. Them1 is highly expressed in thermogenic adipose tissue, where it functions to suppress energy expenditure by limiting rates of fatty acid oxidation. Its expression is also induced markedly in liver in response to high fat feedings, where it suppresses fatty acid oxidation and promotes hepatic glucose production. Mice lacking the gene (Them1-/-) are protected against diet-induced non-alcoholic fatty liver disease (NAFLD), suggesting Them1 as a therapeutic target. The current study was designed to develop small molecule inhibitors of Them1 and to establish their activities in vitro and in cell culture. High-throughput screening combined with counter screening assays were leveraged to identify two lead allosteric inhibitors that selectively inhibited Them1 by binding the START domain. In primary mouse brown adipocytes, these inhibitors promoted fatty acid oxidation, as evidence by increased rates of oxygen consumption. In primary mouse hepatocytes, they similarly promoted fatty acid oxidation, but also reduced glucose production. Optimized Them1 inhibitors could provide an attractive modality for the pharmacologic management of NAFLD and obesity-associated metabolic disorders.

pharmacology and toxicology↗

bioRxiv2022

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository (https://motrpac-data.org/). HighlightsO_LIMulti-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms. C_LIO_LIInterpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise. C_LIO_LIRobust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level. C_LIO_LIDeep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training. C_LIO_LIAll data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages. C_LI

molecular biology↗

bioRxiv2022

Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests

Widespread and frequent testing is critical to prevent the spread of COVID-19, and rapid antigen tests are the diagnostic tool of choice in many settings. With new viral variants continuously emerging and spreading rapidly, the effect of mutations on antigen test performance is a major concern. In response to the spread of variants the National Institutes of Healths Rapid Acceleration of Diagnostics (RADx(R)) initiative created a Variant Task Force to assess the impact of emerging SARS-CoV-2 variants on in vitro diagnostic testing. To evaluate the impact of mutations on rapid antigen tests we developed a lentivirus-mediated mammalian surface-display platform for the SARS-CoV-2 Nucleocapsid protein, the target of the majority of rapid antigen tests. We employed deep mutational scanning (DMS) to directly measure the effect of all possible Nucleocapsid point mutations on antibody binding by 17 diagnostic antibodies used in 11 commercially available antigen tests with FDA emergency use authorization (EUA). The results provide a complete map of the antibodies epitopes and their susceptibility to mutational escape. This approach identifies linear epitopes, conformational epitopes, as well as allosteric escape mutations in any region of the Nucleocapsid protein. All 17 antibodies tested exhibit distinct escape mutation profiles, even among antibodies recognizing the same folded domain. Our data predict no vulnerabilities of rapid antigen tests for detection of mutations found in currently and previously dominant variants of concern and interest. We confirm this using the commercial tests and sequence-confirmed COVID-19 patient samples. The antibody escape mutation profiles generated here serve as a valuable resource for predicting the performance of rapid antigen tests against past, current, as well as any possible future variants of SARS-CoV-2, establishing the direct clinical and public health utility of our system. Further, our mammalian surface-display platform combined with DMS is a generalizable platform for complete mapping of protein-protein interactions.

immunology↗

bioRxiv2021

Evolutionary tuning of a key helix drove androgen selectivity

The genetic and biophysical mechanisms by which new protein functions evolve are central concerns in evolutionary biology and molecular evolution. Despite much speculation, we know little about how protein function evolves. Here, we use ancestral proteins to trace the evolutionary history of ligand recognition in a sub-class of steroid receptors (SRs), an ancient family of ligand-regulated transcription factors that enable long-range cellular communication central to multicellular life. The most ancestral members of this family display promiscuous ligand binding due to their large ligand binding pockets, while more recently evolved SRs tend to have smaller cavities. Less obvious, however, are the forces driving the selectivity of highly similar ligands. A key example is the divergence between the progesterone and androgen receptors (PR, AR), which display a high degree of sequence similarity and yet display differential ligand preferences. This work uses the ancestral steroid receptor 2 (AncSR2), the common ancestor of all 3-ketosteroids and the ancestral androgen receptor 1 (AncAR1), the seminal androgen receptor, to explore the biophysical mechanisms that drove the evolution of androgen specificity. We determine that ligand specificity in androgen receptors is driven by changes in the conformational dynamics of the receptor as well as altered binding pocket interactions, with helix 10 (H10) playing a critical role in tuning ligand specificity.

evolutionary biology↗

bioRxiv2021

Suppression of Fatty Acid Oxidation by Thioesterase Superfamily Member 2 in Skeletal Muscle Promotes Hepatic Steatosis and Insulin Resistance

Thioesterase superfamily member 2 (Them2) is highly expressed in oxidative tissues where it hydrolyzes long chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2-/-) are protected against diet-induced obesity, insulin resistance and hepatic steatosis, liver-specific Them2-/- mice remain susceptible. To explore the contribution of Them2 in extrahepatic tissues, we created mice with Them2 deleted in skeletal muscle (S-Them2-/-), cardiac muscle (C-Them2-/-) or adipose tissue (A-Them2-/-). When fed a high-fat diet, S-Them2-/- but not C-Them2-/- or A-Them2-/- mice exhibited reduced weight gain. Only S-Them2-/- mice exhibited improved glucose homeostasis together with improved insulin sensitivity in skeletal muscle. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2-/- mice were reflected in alterations in skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and the pentose phosphate pathway. Protection from diet-induced hepatic steatosis in S-Them2-/- mice was attributable to increased VLDL triglyceride secretion rates in support of demands of increased muscle fatty acid utilization. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of diet-induced obesity, insulin resistance and hepatic steatosis.

molecular biology↗

bioRxiv2020

Glucocorticoid receptor condensates link DNA-dependent receptor dimerization and transcriptional transactivation

The glucocorticoid receptor (GR) is a ligand-regulated transcription factor (TF) that controls the tissue- and gene-specific transactivation and transrepression of thousands of target genes. Distinct GR DNA binding sequences with activating or repressive activities have been identified, but how they modulate transcription in opposite ways is not known. We show that GR forms phase-separated condensates that specifically concentrate known co-regulators via their intrinsically disordered regions (IDRs) in vitro. A combination of dynamic, multivalent (between IDRs) and specific, stable interactions (between LxxLL motifs and the GR ligand binding domain) control the degree of recruitment. Importantly, GR DNA-binding directs the selective partitioning of co-regulators within GR condensates such that activating DNAs cause enhanced recruitment of co-activators. Our work shows that condensation controls GR function by modulating co-regulator recruitment and provides a mechanism for the up- and down-regulation of GR target genes controlled by distinct DNA recognition elements.

biochemistry↗

bioRxiv2020

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons

The human genome contains vast genetic diversity in the form of naturally occurring coding variants, yet the impact of these variants on protein function and physiology is poorly understood. RGS14 is a multifunctional signaling protein that suppresses synaptic plasticity in dendritic spines of hippocampal neurons. RGS14 also is a nucleocytoplasmic shuttling protein, suggesting that balanced nuclear import/export and dendritic spine localization are essential for RGS14 functions. We identified genetic variants L505R (LR) and R507Q (RQ) located within the nuclear export sequence (NES) of human RGS14. Here we report that RGS14 carrying LR or RQ profoundly impacts protein functions in hippocampal neurons and brain. Following nuclear import, RGS14 nuclear export is regulated by Exportin 1 (XPO1/CRM1). Remarkably, LR and RQ variants disrupt RGS14 binding to Gi1-GDP and XPO1, nucleocytoplasmic equilibrium, and capacity to inhibit LTP. Variant LR accumulates irreversibly in the nucleus, preventing RGS14 binding to G proteins, localization to dendritic spines, and inhibitory actions on LTP induction, while variant RQ exhibits a mixed phenotype. When introduced into mice by CRISPR/Cas9, RGS14-LR protein expression was detected predominantly in the nuclei of neurons within hippocampus, central amygdala, piriform cortex, and striatum, brain regions associated with learning and synaptic plasticity. Whereas mice completely lacking RGS14 exhibit enhanced spatial learning, mice carrying variant LR exhibit normal spatial learning, suggesting that RGS14 may have distinct functions in the nucleus independent from those in dendrites and spines. These findings show that naturally occurring genetic variants can profoundly alter normal protein function, impacting physiology in unexpected ways.

molecular biology↗

bioRxiv2020

Tapping into a phospholipid-LRH-1 axis yields a powerful anti-inflammatory agent with in vivo activity against colitis

Phospholipids are ligands for nuclear hormone receptors (NRs) and regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions greatly improves agonists of liver receptor homolog-1 (LRH-1), a promising therapeutic target for diabetes and colitis. Conventional LRH-1 modulators partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of hybrid molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. The phospholipid-mimicking group improves binding affinity, increases LRH-1 transcriptional activity, promotes coregulator recruitment, and interacts with the targeted LRH-1 residues in crystal structures. The best new agonist markedly improves colonic histopathology and disease-related weight loss in a humanized LRH-1 murine T-cell transfer model of colitis. This is the first evidence of in vivo efficacy for an LRH-1 modulator in colitis, a leap forward in agonist development.

biochemistry↗