RESUMO
Allosteric drugs offer a new avenue for modern drug design. However, the identification of cryptic allosteric sites presents a formidable challenge. Following the allostery nature of residue-driven conformation transition, we propose a state-of-the-art computational pipeline by developing a residue-intuitive hybrid machine learning (RHML) model coupled with molecular dynamics (MD) simulation, through which we can efficiently identify the allosteric site and allosteric modulator as well as reveal their regulation mechanism. For the clinical target ß2-adrenoceptor (ß2AR), we discover an additional allosteric site located around residues D792.50, F2826.44, N3187.45 and S3197.46 and one putative allosteric modulator ZINC5042. Using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and protein structure network (PSN), the allosteric potency and regulation mechanism are probed to further improve identification accuracy. Benefiting from sufficient computational evidence, the experimental assays then validate our predicted allosteric site, negative allosteric potency and regulation pathway, showcasing the effectiveness of the identification pipeline in practice. We expect that it will be applicable to other target proteins.
Assuntos
Sítio Alostérico , Aprendizado de Máquina , Receptores Adrenérgicos beta 2 , Humanos , Regulação Alostérica , Desenho de Fármacos , Simulação de Dinâmica Molecular , Conformação Proteica , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismoRESUMO
Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-Gi complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the ß-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the ß-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR's structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery.
Assuntos
Microscopia Crioeletrônica , Receptores Opioides delta , Receptores Opioides delta/metabolismo , Receptores Opioides delta/agonistas , Receptores Opioides delta/química , Humanos , Animais , Descoberta de Drogas/métodos , Células HEK293 , Transdução de Sinais/efeitos dos fármacos , beta-Arrestinas/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química , Camundongos , Ligantes , Ligação Proteica , Masculino , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Sítios de Ligação , Benzamidas/farmacologia , Benzamidas/química , PiperazinasRESUMO
Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy-driven subtype selectivity for many pharmaceutically important GPCRs.
Assuntos
Entropia , Simulação de Dinâmica Molecular , Receptores Acoplados a Proteínas G , Ligantes , Animais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/química , Humanos , Ligação Proteica , Camundongos , Microscopia Crioeletrônica , Receptores de Canabinoides/metabolismo , Receptores de Canabinoides/química , Sítios de LigaçãoRESUMO
Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and ß-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.
Assuntos
Microscopia Crioeletrônica , Receptor CB1 de Canabinoide , Transdução de Sinais , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/química , Animais , Regulação Alostérica/efeitos dos fármacos , Camundongos , Humanos , Transdução de Sinais/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/genética , Células HEK293 , Relação Estrutura-Atividade , Dronabinol/farmacologia , Dronabinol/química , Dronabinol/análogos & derivados , Cannabis/química , Cannabis/metabolismoRESUMO
Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro34]-NPY and [Leu31, Pro34]-NPY, mainly acting on Y1R, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N-terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through Y2R. However, the recognition mechanisms of Y1R and Y2R with specific agonists remain elusive, thereby hindering subtype receptor-selective drug development. In this study, we report three cryo-electron microscopy (cryo-EM) structures of Gi2-coupled Y1R and Y2R in complexes with NPY, as well as Y1R bound to a selective agonist [Leu31, Pro34]-NPY. Combined with cell-based assays, our study not only reveals the conserved peptide-binding mode of NPY receptors but also identifies an additional sub-pocket that confers ligand selectivity. Moreover, our analysis of Y1R evolutionary dynamics suggests that this sub-pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.
RESUMO
Microglia are endogenous immune cells in the brain, and their pyroptosis and phenotype dichotomy are proved to play roles in neurodegenerative diseases. We investigated whether and how hypoxia affected pyroptosis and phenotype polarization in mouse microglia. Primary mouse microglia and BV2 microglia were exposed to hypoxia. Pyroptosis and M1/M2 phenotype were assessed by measuring gasdermin D truncation and M1/M2 surface marker expression. Mechanisms including purinergic ionotropic receptor (P2XR), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) and NOD-like receptor protein 3 (NLRP3) inflammasome were investigated. We reported hypoxia (90% N2, 5% O2 and 5% CO2) induced pyroptosis and promoted M1 phenotype polarization in primary mouse microglia and BV2 microglia, and the effect appeared after 6 h exposure. Although hypoxia (90% N2, 5% O2 and 5% CO2, 6 h) had no effect on P2X1R and P2X7R expression, it increased P2X4R expression and decreased PGC-1α expression. Interestingly, blockade of P2X4R or P2X7R abolished hypoxia-modulated PGC-1α expression, pyroptosis and M1 polarization. PGC-1α overexpression or overactivation alleviated hypoxia-induced pyroptosis and M1 polarization, while PGC-1α knockdown or deactivation promoted pyroptosis and M1 polarization under normoxic situation. Further, hypoxia induced NLRP3 expression and activated caspase-1 and induced the phosphorylation of NF-κB and reduced the phosphorylation of STAT3/6. NLRP3 inhibitor and caspase-1 inhibitor abolished hypoxia-induced pyroptosis, while NF-κB inhibitor and STAT phosphorylation inducer ameliorated hypoxia-induced M1 polarization. In addition, NF-κB activator and STAT3/6 inhibitor caused microglia M1 polarization under normoxic situation. We concluded in cultured mouse microglia, hypoxia may induce pyroptosis via P2XR/PGC-1α/NLRP3/caspase-1 pathway and trigger M1 polarization through P2XR/PGC-1α/NF-κB/STAT3/6 pathway.
Assuntos
Microglia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Piroptose , Transdução de Sinais , Animais , Piroptose/fisiologia , Microglia/metabolismo , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/fisiologia , Diferenciação Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Hipóxia Celular/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células Cultivadas , Inflamassomos/metabolismo , Fenótipo , Hipóxia/metabolismoRESUMO
Polydopamine is a remarkable molecule that has gained considerable attention for its role in material surface modification, leading to an abundance of research in the biomaterial domain. While its widespread use is well documented, the molecule's potential cellular interactions have been less explored. In particular, dopamine serves as a neurotransmitter and a hormone that interacts with dopamine receptors in cells. Our study sheds light on the previously unexamined interaction between polydopamine and dopamine receptor D1 (DRD1). We discovered that polydopamine, along with its derivatives, such as levodopa and catechol, can activate DRD1âa function previously attributed solely to dopamine. Moreover, we found that polydopamine has the ability to influence cell behavior through the cAMP/PKA pathway, thereby affecting RhoA activity and stress fiber formation. These observations invite further consideration regarding the biological safety of polydopamine in biomedical contexts and also open avenues for new research directions in designing bioactive functional materials.
Assuntos
Dopamina , Levodopa , Dopamina/metabolismo , Polímeros/farmacologia , Indóis/farmacologiaRESUMO
G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.
RESUMO
Glucose is essential to the physiological processes of vertebrates. Mammalian physiological stability requires a relatively stable blood glucose level (~5 mM), whereas other vertebrates have greater flexibility in regulating blood glucose (0.5-25 mM). GCGR family receptors play an important role in vertebrate glucose regulation. Here, we examine the evolution of the GCGR family ligand-receptor systems in different species. Comparatively, we discover that the conserved sequences among GCG family ligands lead to the non-specific activation of ligands across species. In particular, we observe that glucagon-like peptide 1 receptor (GLP1R), glucagon-like peptide 2 receptor (GLP2R), and glucagon-like receptor (GCGLR, also called GCRPR) are arbitrarily activated by other members of the ligand family in birds. Moreover, we reveal that Gallus gallus GLP2 (gGLP2) effectively activates mammalian GLP1R and improves glucose tolerance in diabetic mice. Our study has important implications for understanding blood glucose stabilization in vertebrates and demonstrates that gGLP2 may be a potential drug for treating type 2 diabetes.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglicemia , Animais , Camundongos , Glicemia , Receptores de Glucagon , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ligantes , Glucose , Hiperglicemia/tratamento farmacológico , Mamíferos , Receptor do Peptídeo Semelhante ao Glucagon 1/genéticaRESUMO
Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways2,3. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders4,5. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT1AR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.
Assuntos
Proteínas de Ligação ao GTP , Receptores Acoplados a Proteínas G , Animais , Humanos , Camundongos , Aminas/metabolismo , Anfetamina/metabolismo , Antipsicóticos/química , Antipsicóticos/metabolismo , Sítios de Ligação , Catecolaminas/agonistas , Catecolaminas/química , Catecolaminas/metabolismo , Microscopia Crioeletrônica , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/ultraestrutura , Ligantes , Simulação de Dinâmica Molecular , Mutação , Polifarmacologia , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/ultraestrutura , Especificidade da Espécie , Especificidade por SubstratoRESUMO
Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.
Assuntos
Receptores Acoplados a Proteínas G , Transdução de Sinais , Humanos , Aminas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Esquizofrenia/metabolismoRESUMO
Hydroxycarboxylic acid receptor 2 (HCAR2), a member of Class A G-protein-coupled receptor (GPCR) family, plays a pivotal role in anti-lipolytic and anti-inflammatory effects, establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases. However, the mechanism underlying the signaling of HCAR2 induced by various types of ligands remains elusive. In this study, we elucidate the cryo-electron microscopy (cryo-EM) structure of Gi-coupled HCAR2 in complex with a selective agonist, MK-6892, resolved to a resolution of 2.60 Å. Our structural analysis reveals that MK-6892 occupies not only the orthosteric binding pocket (OBP) but also an extended binding pocket (EBP) within HCAR2. Pharmacological assays conducted in this study demonstrate that the OBP is a critical determinant for ligand selectivity among the HCARs subfamily. Moreover, we investigate the pharmacological properties of the allosteric modulator compound 9n, revealing its probe-dependent behavior on HCAR2 in response to varying orthosteric agonists. Collectively, our findings provide invaluable structural insights that contribute to a deeper understanding of the regulatory mechanisms governing HCAR2 signaling transduction mediated by both orthosteric and allosteric ligands.
Assuntos
Bioensaio , Ácidos Cicloexanocarboxílicos , Microscopia Crioeletrônica , LigantesRESUMO
GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and Gi protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.
Assuntos
Inibição Psicológica , Neuralgia , Humanos , Microscopia Crioeletrônica , Ligação CompetitivaRESUMO
Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body ß-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating Gi/o protein or ß-arrestin effectors. Here, we characterize compound 9n as a Gi-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-Gi pathway. Furthermore, four structures of HCAR2-Gi complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.
Assuntos
Colite , Receptores Acoplados a Proteínas G , Animais , Camundongos , Regulação Alostérica , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP , Inflamação/tratamento farmacológico , Corpos Cetônicos , Niacina/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Mechanical nonreciprocity, or the asymmetric transmission of mechanical quantities between two points in space, is crucial for developing systems that can guide, damp, and control mechanical energy. We report a uniform composite hydrogel that displays substantial mechanical nonreciprocity, owing to direction-dependent buckling of embedded nanofillers. This material exhibits an elastic modulus more than 60 times higher when sheared in one direction compared with the opposite direction. Consequently, it can transform symmetric vibrations into asymmetric ones that are applicable for mass transport and energy harvest. Furthermore, it exhibits an asymmetric deformation when subjected to local interactions, which can induce directional motion of various objects, including macroscopic objects and even small living creatures. This material could promote the development of nonreciprocal systems for practical applications such as energy conversion and biological manipulation.
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G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, regulate a wide array of physiological processes in response to extracellular signals. Although these receptors have proven to be the most successful class of drug targets, their complicated signal transduction pathways (including different effector G proteins and ß-arrestins) and mediation by orthosteric ligands often cause difficulties for drug development, such as on- or off-target effects. Interestingly, identification of ligands that engage allosteric binding sites, which are different from classic orthosteric sites, can promote pathway-specific effects in cooperation with orthosteric ligands. Such pharmacological properties of allosteric modulators offer new strategies to design safer GPCR-targeted therapeutics for various diseases. Here, we explore recent structural studies of GPCRs bound to allosteric modulators. Our inspection of all GPCR families reveals recognition mechanisms of allosteric regulation. More importantly, this review highlights the diversity of allosteric sites and presents how allosteric modulators control specific GPCR pathways to provide opportunities for the development of new valuable agents.
Assuntos
Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Ligantes , Regulação Alostérica , Sítios de LigaçãoRESUMO
The complement system plays an important role in the innate immune response to invading pathogens. The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and ß-arrestin signaling pathways. Dysfunction of the C5a-C5aR1 axis is linked to numerous inflammatory and immune-mediated diseases, but the structural basis for activation and biased signaling of C5aR1 remains elusive. Here, we present cryo-electron microscopy structures of the activated wild-type C5aR1-Gi protein complex bound to each of the following: C5a, the hexapeptidic agonist C5apep, and the G protein-biased agonist BM213. The structures reveal the landscape of the C5a-C5aR1 interaction as well as a common motif for the recognition of diverse orthosteric ligands. Moreover, combined with mutagenesis studies and cell-based pharmacological assays, we deciphered a framework for biased signaling using different peptide analogs and provided insight into the activation mechanism of C5aR1 by solving the structure of C5aR1I116A mutant-Gi signaling activation complex induced by C089, which exerts antagonism on wild-type C5aR1. In addition, unusual conformational changes in the intracellular end of transmembrane domain 7 and helix 8 upon agonist binding suggest a differential signal transduction process. Collectively, our study provides mechanistic understanding into the ligand recognition, biased signaling modulation, activation, and Gi protein coupling of C5aR1, which may facilitate the future design of therapeutic agents.
Assuntos
Receptor da Anafilatoxina C5a , Transdução de Sinais , Microscopia Crioeletrônica , Imunidade Inata , Complemento C5a/metabolismoRESUMO
INTRODUCTION: For women with epilepsy of reproductive age, antiseizure medications (ASMs) are associated with an increased risk of offspring malformations. There are safety concerns for most anti-seizure medications in the perinatal period, and there is a clear need to identify safe medications. ASMs must transport through biological barriers to exert toxic effects on the fetus, and transporters play essential roles in trans-barrier drug transport. Therefore, it is vital to understand the distribution and properties of ASM-related transporters in biological barriers. AREAS COVERED: This study reviews the structure, transporter distribution, and properties of the blood-brain, placental, and blood-milk barrier, and summarizes the existing evidence for the trans-barrier transport mechanism of ASMs and standard experimental models of biological barriers. EXPERT OPINION: Ideal ASMs in the perinatal period should have the following characteristics: 1) Increased transport through the blood-brain barrier, and 2) Reduced transport of the placental and blood-milk barriers. Thus, only low-dose or almost no antiseizure medication could enter the fetus's body, which could decrease medication-induced fetal abnormalities. Based on the stimulated structure and molecular docking, we propose a development strategy for new ASMs targeting transporters of biological barriers to improve the perinatal treatment of female patients with epilepsy.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Placenta , Feminino , Humanos , Gravidez , Anticonvulsivantes/efeitos adversos , Barreira Hematoencefálica , Simulação de Acoplamento Molecular , Guias como AssuntoRESUMO
Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors.