Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Recent advances on the inhibition of human solute carriers: Therapeutic implications and mechanistic insights.

ABSTRACT: Solute carriers (SLCs) are membrane transport proteins tasked with mediating passage of hydrophilic molecules across lipid bilayers. Despite the extensive roles played in all aspects of human biology, SLCs remain vastly under-explored as therapeutic targets. In this brief review, we first discuss a few successful cases of drugs that exert their mechanisms of action through inhibition of human SLCs, and introduce select examples of human SLCs that have untapped therapeutic potential. We then highlight two recent structural studies which uncovered detailed structural mechanisms of inhibition exhibited against two different human major facilitator superfamily (MFS) transporters of clinical relevance.

SUBMITTER: Wright NJ

PROVIDER: S-EPMC9763051 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Recent advances on the inhibition of human solute carriers: Therapeutic implications and mechanistic insights.

Wright Nicholas J NJ Lee Seok-Yong SY

Current opinion in structural biology 20220426

Solute carriers (SLCs) are membrane transport proteins tasked with mediating passage of hydrophilic molecules across lipid bilayers. Despite the extensive roles played in all aspects of human biology, SLCs remain vastly under-explored as therapeutic targets. In this brief review, we first discuss a few successful cases of drugs that exert their mechanisms of action through inhibition of human SLCs, and introduce select examples of human SLCs that have untapped therapeutic potential. We then high ...[more]

PMID: 35487145

Similar Datasets

Extracorporeal Photochemotherapy: Mechanistic Insights Driving Recent Advances and Future Directions.

Project description:Dendritic cells (DCs) are professional antigen-presenting cells, necessary for the initiation and maintenance of antigen-specific immunity and tolerance. Decades of research have been driven by hopes to harness the immunological capabilities of DCs and achieve physiological partnership with the immune system for therapeutic ends. Potential applications for DC-based immunotherapy include treatments for cancer, autoimmune disorders, and infectious diseases. However, DCs have poor availability in peripheral and lymphoid tissues and have poor survivability in culture, leading to the development of multiple strategies to generate and manipulate large numbers of DCs ex vivo. Among these is Extracorporeal Photopheresis (ECP), a widely used cancer immunotherapy. Recent advancements have uncovered that stimulation of monocyte-to-DC maturation via physiologic inflammatory signaling lies at the mechanistic core of ECP. Here, we describe the landscape of DC-based immunotherapy, the historical context of ECP, the current mechanistic understanding of ex vivo monocyte-to-DC maturation in ECP, and the implications of this understanding on making scientifically driven improvements to modern ECP protocols and devices.

| S-EPMC7087063 | biostudies-literature

Cardiorenal interactions in heart failure: insights from recent therapeutic advances.

Project description:Heart failure is a syndrome that may develop when cardiovascular disease progresses or is insufficiently treated and associated with a poor quality of life, high mortality rates, and increased healthcare expenditures. Prevention and treatment of heart failure are therefore of utmost importance. New therapies in patients with cardiovascular disease have recently been shown to be effective in the prevention and sometimes treatment of heart failure, and additional research is underway. Specifically, in high-risk patients with either (a combination of) diabetes, chronic kidney disease, and/or heart failure, three specific drug classes [sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1-RAs), and non-steroidal mineralocorticoid receptor antagonists (MRAs)] have taken centre stage in therapeutic approach for these high cardiovascular risk patients. The commonality of these drugs is the finding that they improve cardiovascular and renal endpoints across the cardiorenal continuum and SGTL2i have already proved effective in all subtypes of heart failure, while we await data on non-steroidal MRA therapy in heart failure. The story may be different for GLP-1-RA in patients with established heart failure, but these drugs are effective in reducing cardiovascular events in patients with diabetes. Taken together, these new therapies advance the treatment and improve the associated outcomes of patients with cardiorenal disease and diabetes, with similar characteristics and effectiveness in different conditions.

| S-EPMC11472538 | biostudies-literature

Comparison of human solute carriers.

Project description:Solute carriers are eukaryotic membrane proteins that control the uptake and efflux of solutes, including essential cellular compounds, environmental toxins, and therapeutic drugs. Solute carriers can share similar structural features despite weak sequence similarities. Identification of sequence relationships among solute carriers is needed to enhance our ability to model individual carriers and to elucidate the molecular mechanisms of their substrate specificity and transport. Here, we describe a comprehensive comparison of solute carriers. We link the proteins using sensitive profile-profile alignments and two classification approaches, including similarity networks. The clusters are analyzed in view of substrate type, transport mode, organism conservation, and tissue specificity. Solute carrier families with similar substrates generally cluster together, despite exhibiting relatively weak sequence similarities. In contrast, some families cluster together with no apparent reason, revealing unexplored relationships. We demonstrate computationally and experimentally the functional overlap between representative members of these families. Finally, we identify four putative solute carriers in the human genome. The solute carriers include a biomedically important group of membrane proteins that is diverse in sequence and structure. The proposed classification of solute carriers, combined with experiment, reveals new relationships among the individual families and identifies new solute carriers. The classification scheme will inform future attempts directed at modeling the structures of the solute carriers, a prerequisite for describing the substrate specificities of the individual families.

| S-EPMC2866268 | biostudies-literature

Role of Glyoxalase 1 (Glo1) and methylglyoxal (MG) in behavior: recent advances and mechanistic insights.

Project description:Glyoxalase 1 (GLO1) is a ubiquitous cellular enzyme that participates in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis that induces protein modification (advanced glycation end-products, AGEs), oxidative stress, and apoptosis. The concentration of MG is elevated under high-glucose conditions, such as diabetes. As such, GLO1 and MG have been implicated in the pathogenesis of diabetic complications. Recently, findings have linked GLO1 to numerous behavioral phenotypes, including psychiatric diseases (anxiety, depression, schizophrenia, and autism) and pain. This review highlights GLO1's association with behavioral phenotypes, describes recent discoveries that have elucidated the underlying mechanisms, and identifies opportunities for future research.

| S-EPMC3500958 | biostudies-other

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications.

Project description:The development of coagulation factor VIII (FVIII) inhibitory antibodies is a serious complication in hemophilia A (HA) patients after FVIII replacement therapy. Inhibitors render regular prophylaxis ineffective and increase the risk of morbidity and mortality. Immune tolerance induction (ITI) regimens have become the only clinically proven therapy for eradicating these inhibitors. However, this is a lengthy and costly strategy. For HA patients with high titer inhibitors, bypassing or new hemostatic agents must be used in clinical prophylaxis due to the ineffective ITI regimens. Since multiple genetic and environmental factors are involved in the pathogenesis of inhibitor generation, understanding the mechanisms by which inhibitors develop could help identify critical targets that can be exploited to prevent or eradicate inhibitors. In this review, we provide a comprehensive overview of the recent advances related to mechanistic insights into anti-FVIII antibody development and discuss novel therapeutic approaches for HA patients with inhibitors.

| S-EPMC9774473 | biostudies-literature

Recent advances in human norovirus research and implications for candidate vaccines.

Project description:IntroductionNoroviruses are a leading cause of acute gastroenteritis worldwide. An estimated 21 million illnesses in the United States and upwards of 684 million illnesses worldwide are attributed to norovirus infection. There are no licensed vaccines to prevent norovirus, but several candidates are in development.Areas coveredWe review recent advances in molecular epidemiology of noroviruses, immunology, and in-vitro cultivation of noroviruses using human intestinal enteroids. We also provide an update on the status of norovirus vaccine candidates.Expert opinionMolecular epidemiological studies confirm the tremendous genetic diversity of noroviruses, the continuous emergence of new recombinant strains, and the predominance of GII.4 viruses worldwide. Duration of immunity, extent of cross protection between different genotypes, and differences in strain distribution for young children compared with adults remain key knowledge gaps. Recent discoveries regarding which epitopes are targeted by neutralizing antibodies using the novel in vitro culture of human noroviruses in human intestinal enteroids are enhancing our understanding of mechanisms of protection and providing guidance for vaccine development. A future norovirus vaccine has the potential to substantially reduce the burden of illnesses due to this ubiquitous virus.

| S-EPMC10760411 | biostudies-literature

Molecular mechanisms of pain in acute pancreatitis: recent basic research advances and therapeutic implications.

Project description:Although severe abdominal pain is the main symptom of acute pancreatitis, its mechanisms are poorly understood. An emerging body of literature evidence indicates that neurogenic inflammation might play a major role in modulating the perception of pain from the pancreas. Neurogenic inflammation is the result of a crosstalk between injured pancreatic tissue and activated neurons, which leads to an auto-amplification loop between inflammation and pain during the progression of acute pancreatitis. In this review, we summarize recent findings on the role of neuropeptides, ion channels, and the endocannabinoid system in acute pancreatitis-related pain. We also highlight potential therapeutic strategies that could be applied for managing severe pain in this disease.

| S-EPMC10771850 | biostudies-literature

Recent Therapeutic Advances in Pituitary Carcinoma.

Project description:Pituitary carcinoma (PC) is a rare, aggressive malignancy that comprises 0.1-0.2% of all pituitary tumors. PC is defined anatomically as a pituitary tumor that metastasizes outside the primary intrasellar location as noncontiguous lesions in the central nervous system or as metastases to other organs. Similar to pituitary adenoma, PC originates from various cell types of the pituitary gland and can be functioning or nonfunctioning, with the former constituting the majority of the cases. Compression of intricate skull-based structures, excessive hormonal secretion, impaired pituitary function from therapy, and systemic metastases lead to debilitating symptoms and a poor survival outcome in most cases. PC frequently recurs despite multimodality treatments, including surgical resection, radiotherapy, and biochemical and cytotoxic treatments. There is an unmet need to better understand the pathogenesis and molecular characterization of PC to improve therapeutic strategies. As our understanding of the role of signaling pathways in the tumorigenesis of and malignant transformation of PC evolves, efforts have focused on targeted therapy. In addition, recent advances in the use of immune checkpoint inhibitors to treat various solid cancers have led to an interest in exploring the role of immunotherapy for the treatment of aggressive refractory pituitary tumors. Here, we review our current understanding of the pathogenesis, molecular characterization, and treatment of PC. Particular attention is given to emerging treatment options, including targeted therapy, immunotherapy, and peptide receptor radionuclide therapy.

| S-EPMC10195013 | biostudies-literature

A substrate-based ontology for human solute carriers.

Project description:Solute carriers (SLCs) are the largest family of transmembrane transporters in the human genome with more than 400 members. Despite the fact that SLCs mediate critical biological functions and several are important pharmacological targets, a large proportion of them is poorly characterized and present no assigned substrate. A major limitation to systems-level de-orphanization campaigns is the absence of a structured, language-controlled chemical annotation. Here we describe a thorough manual annotation of SLCs based on literature. The annotation of substrates, transport mechanism, coupled ions, and subcellular localization for 446 human SLCs confirmed that ~30% of these were still functionally orphan and lacked known substrates. Application of a substrate-based ontology to transcriptomic datasets identified SLC-specific responses to external perturbations, while a machine-learning approach based on the annotation allowed us to identify potential substrates for several orphan SLCs. The annotation is available at https://opendata.cemm.at/gsflab/slcontology/. Given the increasing availability of large biological datasets and the growing interest in transporters, we expect that the effort presented here will be critical to provide novel insights into the functions of SLCs.

| S-EPMC7374931 | biostudies-literature

Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications.

Project description:Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are members of the 2-oxoglutarate dependent non-heme iron dioxygenases. Due to their physiological roles in regulation of HIF-1? stability, many efforts have been focused on searching for selective PHD inhibitors to control HIF-1? levels for therapeutic applications. In this review, we first describe the structure of PHD2 as a molecular basis for structure-based drug design (SBDD) and various experimental methods developed for measuring PHD activity. We further discuss the current status of the development of PHD inhibitors enabled by combining SBDD approaches with high-throughput screening. Finally, we highlight the clinical implications of small molecule PHD inhibitors.

| S-EPMC6332328 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data