Understanding Cell Penetration of Cyclic Peptides

Chemical Reviews, Год журнала: 2019, Номер 119(17), С. 10241 - 10287

Опубликована: Май 14, 2019

Approximately 75% of all disease-relevant human proteins, including those involved in intracellular protein-protein interactions (PPIs), are undruggable with the current drug modalities (i.e., small molecules and biologics). Macrocyclic peptides provide a potential solution to these targets because their larger sizes (relative conventional molecules) endow them capability binding flat PPI interfaces antibody-like affinity specificity. Powerful combinatorial library technologies have been developed routinely identify cyclic as potent, specific inhibitors against proteins targets. However, exception very set sequences, vast majority impermeable cell membrane, preventing application This Review examines common structural features that render most membrane impermeable, well unique allow minority sequences enter interior by passive diffusion, endocytosis/endosomal escape, or other mechanisms. We also present state knowledge about molecular mechanisms penetration, various strategies for designing cell-permeable, biologically active targets, assay methods available quantify cell-permeability.

Язык: Английский

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A guide to plasma membrane solute carrier proteins

FEBS Journal, Год журнала: 2020, Номер 288(9), С. 2784 - 2835

Опубликована: Авг. 24, 2020

This review aims to serve as an introduction the solute carrier proteins (SLC) superfamily of transporter and their roles in human cells. The SLC currently includes 458 transport 65 families that carry a wide variety substances across cellular membranes. While members this are found throughout organelles, focuses on transporters expressed at plasma membrane. At cell surface, may be viewed gatekeepers milieu, dynamically responding different metabolic states. With altered metabolism being one hallmarks cancer, we also briefly surface play development progression cancer through influence regulating environmental conditions.

Язык: Английский

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The influence of the gut microbiota on the bioavailability of oral drugs

Acta Pharmaceutica Sinica B, Год журнала: 2020, Номер 11(7), С. 1789 - 1812

Опубликована: Сен. 28, 2020

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy many drugs is limited their unsatisfactory bioavailability in gastrointestinal tract. One critical most overlooked factors symbiotic gut microbiota that can modulate by participating biotransformation drugs, influencing drug transport process altering some properties. In this review, we summarized existing research investigating possible relationship between which may provide great ideas useful instructions for design novel delivery systems or achievement personalized medicine.

Язык: Английский

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The Concise Guide to PHARMACOLOGY 2023/24: Transporters

British Journal of Pharmacology, Год журнала: 2023, Номер 180(S2)

Опубликована: Окт. 1, 2023

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. provides concise overviews, mostly tabular format, key properties approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There an emphasis on selective pharmacology (where available), plus links open access knowledgebase source targets their ligands ( https://www.guidetopharmacology.org/ ), which more detailed views target ligand properties. Although constitutes almost 500 pages, material presented substantially reduced compared information website. It a permanent, citable, point‐in‐time record that will survive database updates. full contents section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16182 . Transporters are one six major pharmacological into divided, others being: G protein‐coupled receptors, ion channels, nuclear hormone catalytic receptors enzymes. These nomenclature guidance summary best available tools, alongside references suggestions for further reading. landscape format designed facilitate comparison related from contemporary mid‐2023, supersedes data 2021/22, 2019/20, 2017/18, 2015/16 2013/14 Guides previous Receptors Channels. produced close conjunction Nomenclature Standards Committee International Union Basic Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification human where appropriate.

Язык: Английский

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Metabolic mapping of the human solute carrier superfamily

Molecular Systems Biology, Год журнала: 2025, Номер unknown

Опубликована: Май 12, 2025

Abstract Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked function identity. Despite their key role, individual functions SLC superfamily members were not evaluated systematically. We determined transcriptional profiles upon overexpression knock-out or wild-type isogenic cell backgrounds for 378 SLCs 441 SLCs, respectively. Targeted metabolomics provided a fingerprint 189 intracellular metabolites, while transcriptomics offered insights into programs modulated by expression. Beyond 102 directly related known substrates, we identified putative substrates pathway connections 71 without previously annotated bona fide including SLC45A4 as new polyamine transporter. By comparing molecular profiles, functionally groups, some with distinct impacts on osmolyte balancing glycosylation. The assessment human genes presented here may serve blueprint other systematic studies supports future investigations functional roles SLCs.

Язык: Английский

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Direct protein-lipid interactions shape the conformational landscape of secondary transporters

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Окт. 2, 2018

Abstract Secondary transporters undergo structural rearrangements to catalyze substrate translocation across the cell membrane – yet how such conformational changes happen within a lipid environment remains poorly understood. Here, we combine hydrogen-deuterium exchange mass spectrometry (HDX-MS) with molecular dynamics (MD) simulations understand lipids regulate of secondary at level. Using homologous XylE, LacY and GlpT from Escherichia coli as model systems, discover that conserved networks charged residues act switches drive transition between different states. We reveal these are regulated by interactions surrounding phospholipids show phosphatidylethanolamine interferes formation favors an inward-facing state. Overall, this work provides insights into importance in shaping landscape important class transporters.

Язык: Английский

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CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Фев. 26, 2018

Abstract Na + -coupled acid–base transporters play essential roles in human biology. Their dysfunction has been linked to cancer, heart, and brain disease. High-resolution structures of mammalian are not available. The sodium-bicarbonate cotransporter NBCe1 functions multiple organs its mutations cause blindness, abnormal growth blood chemistry, migraines, impaired cognitive function. Here, we have determined the structure membrane domain dimer at 3.9 Å resolution by cryo electron microscopy. Our atomic model functional mutagenesis revealed ion accessibility pathway coordination site, latter containing residues involved disease-causing mutations. We identified a small number within site whose modification transformed into an anion exchanger. data suggest that symporters exchangers utilize comparable transport machinery subtle differences their substrate-binding regions very significant effects on mode.

Язык: Английский

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The Druggability of Solute Carriers

Journal of Medicinal Chemistry, Год журнала: 2019, Номер 63(8), С. 3834 - 3867

Опубликована: Ноя. 27, 2019

The transport of materials across membranes is a vital process for all aspects cellular function, including growth, metabolism, and communication. Protein transporters are the molecular gates that control this movement serve as key points regulation these processes, thus representing an attractive class therapeutic targets. With more than 400 members, solute carrier (SLC) membrane proteins largest family transporters, yet, they pharmacologically underexploited relative to other protein families many available chemical tools possess suboptimal selectivity efficacy. Fortuitously, there increased interest in elucidating physiological roles SLCs well growing recognition their potential. This Perspective provides overview SLC superfamily, biochemical functional features, various human diseases. In particular, we explore efforts associated challenges toward drugging SLCs, highlight opportunities future drug discovery.

Язык: Английский

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Xenobiotic metabolism and transport in Caenorhabditis elegans

Journal of Toxicology and Environmental Health Part B, Год журнала: 2021, Номер 24(2), С. 51 - 94

Опубликована: Фев. 17, 2021

Caenorhabditis elegans has emerged as a major model in biomedical and environmental toxicology. Numerous papers on toxicology pharmacology C. have been published, this species now adopted by investigators academic toxicology, pharmacology, drug discovery labs. also attracted the interest of governmental regulatory agencies charged with evaluating safety chemicals. However, major, fundamental aspect toxicological science remains underdeveloped elegans: xenobiotic metabolism transport processes that are critical to understanding toxicokinetics toxicodynamics, extrapolation other species. The aim review was initially briefly describe history trajectory use pharmacological studies. Subsequently, physical barriers chemical uptake role worm microbiome transformation were described. Then what is not known regarding classic Phase I, II, III performed. In addition, following discussed (1) regulation metabolism; (2) published for specific chemicals; (3) genetic diversity these elegans. Finally, placed an evolutionary context; key areas future research highlighted; implications extrapolating toxicity results discussed.

Язык: Английский

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Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis

Cell chemical biology, Год журнала: 2020, Номер 27(6), С. 728 - 739.e9

Опубликована: Май 7, 2020

With more than 450 members, the solute carrier (SLC) group of proteins represents largest class transporters encoded in human genome. Their several-pass transmembrane domain structure and hydrophobicity contribute to orphan status many SLCs, devoid known cargos or chemical inhibitors. We report that SLC belonging different families subcellular compartments are amenable induced degradation by heterobifunctional ligands. Engineering endogenous alleles via tag (dTAG) technology enabled control abundance transporter protein, SLC38A2. Moreover, we design d9A-2, a chimeric compound engaging several members SLC9 family leading their degradation. d9A-2 impairs cellular pH homeostasis promotes cell death range cancer lines. These findings open era SLC-targeting degraders demonstrate potential access multi-pass localizations chemically exploitable machinery.

Язык: Английский

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