G Protein Coupled

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G protein-coupled receptors: structure- and function-based drug discovery
As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are eye-witnessing tremendous progresses made recently in the understanding of their structure–function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.
G protein-coupled receptors (GPCRs) represent the largest protein family encoded by the human genome. Located on the cell membrane, they transduce extracellular signals into key physiological effects.1 Their endogenous ligands include odors, hormones, neurotransmitters, chemokines, etc., varying from photons, amines, carbohydrates, lipids, peptides to proteins. GPCRs have been implicated in a large number of diseases, such as type 2 diabetes mellitus (T2DM), obesity, depression, cancer, Alzheimer’s disease, and many others.2 Activated by external signals through coupling to different G proteins or arrestins, GPCRs elicit cyclic adenosine 3,5-monophosphate (cAMP) response, calcium mobilization, or phosphorylation of extracellular regulated protein kinases 1/2 (pERK1/2).3 The seven-transmembrane protein property endows them easy to access, while the diversified downstream signaling pathways make them attractive for drug development.4 The human GPCR family is divided into classes A (rhodopsin), B (secretin and adhesion), C (glutamate), and F (Frizzled) subfamilies according to their amino acid sequences (Fig. 1). Of the 826 human GPCRs, approximately 350 non-olfactory members are regarded as druggable and 165 of them are validated drug targets (Fig. 1 and Table S1).4,5,6 Latest statistical data indicate that 527 Food and Drug Administration (FDA)-approved drugs4 and ∼60 drug candidates currently in clinical trials target GPCRs (Table S1).5
Phylogenetic tree of GPCRs as drug targets. Node represents GPCR named according to its gene name. Receptors with approved drugs on the market are highlighted by color. GPCRs are organized according to GPCR database.4 Approved drug list was derived from previous publications,4,11 complemented by additional search of newly approved entities at Drugs@FDA (accessdata.fda.gov) until June 2020. See Table S2 for details
Started with crystal structure determination and accelerated by cryo-electron microscopy (cryo-EM) technology, three-dimensional (3D) structural studies on a variety of GPCRs in complex with ligands, G proteins/arrestins, or both7,8,9,10 (involving 455 structures from 82 different receptors) significantly deepened our knowledge of molecular mechanisms of signal transduction. Novel insights into ligand recognition and receptor activation are gained from inactive, transitional, active, and apo states, thereby offering new opportunities for structure-based drug design (SBDD).11 Pharmacological parameters such as cAMP accumulation, calcium flux, ERK phosphorylation, arrestin recruitment, and G protein interaction,12,13 are commonly used to evaluate ligand action and biased signaling. Ligand-binding kinetics and signaling timing render another dimension for interpreting signal bias profiles and link in vitro bioactivities with in vivo effects.14 In this process, a series of biased and allosteric modulators were discovered by rational design, ligand screening, and pharmacological assessment leading to the identification of novel binding sites or action modes.15,16
Apart from crystallography and cryo-EM, the striking advancement in GPCR biology is also attributable to the deployment of powerful technologies such as nuclear magnetic resonance (NMR), hydrogen–deuterium exchange (HDX), fluorescence resonance energy transfer, bioluminescence resonance energy transfer, surface plasmon resonance, single molecule fluorescence, CRISPR/Cas9, artificial intelligence, etc. This review systematically summarizes the latest information on this important drug target family to cover both basic and translational sciences in the context of drug discovery and development.
Class A GPCRs, the so called “rhodopsin-like family” consisting of 719 members, are divided into several subgroups: aminergic, peptide, protein, lipid, melatonin, nucleotide, steroid, alicarboxylic acid, sensory, and orphan.17 They have a conventional transmembrane domain (TMD) that forms ligand-binding pocket and additional eight helices with a palmitoylated cysteine at the C terminal.18,19 Given the wide range of their physiological functions, this class of receptors is the most targeted therapeutically among all other classes. By manually curating Drugs@FDA original New Drug Application (NDA) and Biologic License Application (BLA) database (data extracted from August 2017 to June 2020) and cross-referencing with Drugbank,20 IUPHAR and ChemBL databases, we were able to find the approved drugs associated with this class.
Over 500 GPCR drugs target class A and many of them act at >1 receptor: 75% are made against aminergic receptors and 10% for peptidic ligand receptors with indications ranging from analgesics, allergies, cardiovascular diseases, hypertension, pulmonary diseases, depression, migraine, glaucoma, Parkinson’s disease to schizophrenia, cancer-related fatigue, etc. Approximately 500 novel drug candidates are in clinical trials. Of them, 134 are for peptide-activated GPCRs, while small molecules still occupy the majority. It is noted that 6% of class A members are sensory and alicarboxylic acid receptors that have broad untapped therapeutic potentials (Table S1). Chemokine, prostanoid and melanocortin receptors constitute >8% clinical trial targets in this class.
In the past 3 years, about 20 NDAs were approved targeting mostly peptide and aminergic receptors (Table 1). Siponimod and ozanimod provide alternatives to fingolimod (approved in 2010) for treating relapsing forms of multiple sclerosis by modulating sphingosine-1-phosphate receptor. Two radiolabeled ligands, gallium 68 dotatoc and lutetium 177 dotatate, have been approved for neuroendocrine tumor and pancreatic gastrointestinal cancer diagnosis, respectively. Pitolisant, a selective inverse agonist of histamine receptor, is used to treat narcolepsy-related daytime sleepiness, while lemborexant, an orexin receptor antagonist, is used for insomnia management. Gilteritinib (ASP2215) is a small molecule inhibitor of tyrosine kinase. However, it also antagonizes serotonin receptors without any reported pharmacological consequences. Revefenacin is a long-acting antagonist of muscarinic acetylcholine receptors (mAChRs) indicated for chronic obstructive pulmonary disease. Amisulpride, trialed for antiemetic and schizophrenia, was finally approved for antiemetic in 2020. This molecule is acting as an antagonist against dopamine and serotonin receptors. Fosnetupitant, a prodrug of netupitant, was approved for chemotherapy-induced nausea and vomiting. Cysteamine treats radiation sickness via modifying action of neuropeptide Y receptor. Cannabidiol is one the active constituents of the Cannabis plant and was trialed for schizophrenia, graft versus host disease, and anticonvulsant. It was eventually approved in 2018 for the treatment of severe forms of epilepsy—Lennox–Gastaut syndrome and Dravet syndrome. Meanwhile, fostamatinib, indicated for chronic immune thrombocytopenia, targets >300 receptors and enzymes, including adenosine receptor A3.
This class of GPCRs is divided into two subfamilies: secretin (B1) and adhesion (B2), containing 15 and 33 members, respectively.4,21 Secretin subfamily members are characteristic of large extracellular domains (ECDs) and bind to vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), corticotropin-releasing factor (CRF), parathyroid peptide hormone (PTH), growth hormone-releasing hormone (GHRH), calcitonin gene-related peptide (CGRP), glucagon, and glucagon-like peptides (GLPs), respectively. Adhesion subfamily has nine subgroups, possessing unique N-terminal motifs, such as epidermal growth factor, cadherin, and immunoglobulin domains. They are distinguished from other GPCRs due to their roles in cell adhesion and migration.22,23 Apart from the long N-terminal domain, other unique features of the B2 subfamily are the GPCR autoproteolysis-inducing domain and the proteolysis site that are responsible for signaling activation through a Stachel sequence (a tethered agonist) and producing N-terminal fragment (NTF) and C-terminal fragment. The hallmarks of the B2 GPCR subfamily are a two-step activation model, the ligand–NTF interaction and the Stachel signaling/basal activity. Adhesion receptors can also signal independently of fragment dissociation and this has complicated pharmacological consequences.22,24,25
In this class, receptors of glucagon family peptides, followed by CGRP, PTH, GHRH, CRF, VIP, and PACAP, constitute major targets for therapeutic intervention (Table S1) of various diseases, including obesity, T2DM, osteoporosis, migraine, depression, and anxiety.26,27
To date, multiple GLP-1 receptor (GLP-1R) agonists have been developed by a combination of selective amino acid substitutions, enzymatic cleavage blockade, and conjugation to entities that increase binding to plasma proteins. These methods not only slow down fast renal clearance of the peptides but also extend their half-lives. Dose-dependent side effects such as nausea and gastrointestinal adverse events are the main drawbacks that are becoming more of a compliant with dose scaling.28,29 For instance, one newly approved GLP-1R agonist, semaglutide, has a noticeable half-life of 168 h thereby allowing weekly subcutaneous administration, while oral semaglutide (approved in 2019) formulated using absorption enhancer shows a similar half-life but is dosed daily with reported side effects (Table 2).30,31
One of the latest approaches to develop more efficacious therapeutics against T2DM and obesity relates to dual- and tri-agonists targeting two or more of GLP-1R, glucagon receptor (GCGR), and glucose-dependent insulinotropic peptide receptor (GIPR). Many of them are currently in different phases of clinical trials (Table 3).32,33,34,35,36,37 Of note, in this receptor family, GLP-2 stimulates intestinal growth and an approved GLP-2R agonist, teduglutide, is used to treat short bowel syndrome.38
CGRP family has a considerable clinical relevance. For instance, pramlintide that targets amylin receptor is utilized to treat both type 1 and type 2 diabetes. Salmon calcitonin has been explored as a treatment for Paget’s disease and metabolic disorders.39,40,41 Furthermore, the association of migraine and CGRP elevation led to FDA-approved monoclonal antibodies (mAbs) against its receptor, e.g., erenumab and eptinezumab, as well as several small molecule antagonists such as rimegepant and ubrogepant (Table 2).42,43 Two approved diagnostic agents are analogs of CRF (corticorelin ovine triflutate peptide) and GHRH (sermorelin) for diagnosis of Cushing’s disease or ectopic adrenocorticotropic hormone syndrome and growth hormone deficiency, respectively.44,45 Tesamorelin, another synthetic form of GHRH, was approved in 2010 to treat human immunodeficiency virus (HIV)-associated lipodystrophy.44
PTH analogs, teriparatide and abaloparatide, were approved in 2002 and 2017, respectively, for postmenopausal osteoporosis with similar side effects. However, abaloparatide binds to parathyroid hormone 1 receptor (PTH1R) with higher affinity and selectivity that resulted in greater bone density.46
No therapeutic agent from the adhesion subfamily has entered clinical trial to date (Table S1).2,4,47 Although, adhesion GPCRs have shown coupling to heterotrimeric G proteins, the major challenge associated with this family is connecting G protein signals with biological activities.24 This subfamily was found to play functional roles in the immune, cardiovascular, respiratory, nervous, musculoskeletal, reproductive, renal, integumentary, sensory, endocrine, and gastrointestinal systems, with implications in neurological and neoplastic disorders.24 For instance, ADGRG1 and ADGRF1 are considered as potential drug targets due to their extensive pathogenetic involvement. Two ADGRG1/ADGRG5 modulators, dihydromunduletone and 3-α-acetoxydihydrodeoxygedunin developed via drug screening efforts, showed disease-related efficacy changes thereby calling for exploration of their activities in a pathological environment.24,25 However, associated drug resistance may not only hamper disease but also offer insights into potential mechanisms of such resistance and strategies to tackle it.
Class C (glutamate) contains 22 receptors, which are further divided into 5 subfamilies including 1 calcium-sensing receptor (CaSR), 2 gamma-aminobutyric acid (GABA) type B receptors (GABAB1 and GABAB2), 3 taste 1 receptors (TS1R1–3), 8 metabotropic glutamate receptors (mGluR1–8), and 8 orphan GPCRs.48 The distinctive features of glutamate subfamily are their large ECD and obligated constitutive dimer for receptor activation.49 The structural information of ECD indicates the roles of conserved venus fly trap (VFT) and cysteine-rich domain (CRD) on the ligand-binding site. Two conserved disulfide bonds between VFT domains stabilize the homodimers or heterodimers of class F GPCRs.50 The cryo-EM structures of the first full-length mGluR551 and more recently the GABABRs further revealed their assembly mechanism and overall architecture.52,53,54,55 To date, 16 drugs have been approved by the FDA targeting 8 class C GPCRs. As archetypal receptors, mGluRs mediate the stimulus of agonists such as glutamate and their malfunction are implicated in various diseases, including cancer, schizophrenia, depression, and movement disorders. Acamprosate, an antagonist of mGluR5, was launched in 2004 as an anti-neoplastic agent.56 In fact, mGluRs have been vigorously pursued as therapeutic targets and there are 15 drug candidates undergoing clinical trials at present for pain, migraine, Parkinson’s disease, Fragile X syndrome, etc. Although allosteric modulators of class C have attracted significant development efforts involving 8 clinical trial stage compounds [2 positive (PAM) and 6 negative (NAM) allosteric modulators], the only success is cinacalcet, a small molecule PAM of CaSR approved in 2004 for hyperparathyroidism and calcimimetics.57
Only one class F GPCR (smoothed receptor SMO) has been validated as a drug target whose small molecule antagonists were approved as anti-neoplastic agents.58 Other 10 members of this class are all Frizzled receptors (FZD1–10), which mediate Wnt signaling and are essential for embryonic development and adult organisms. FZDs together with cognate Hedgehog and Wnt signal are associated with a variety of diseases such as cancer, fibrosis, and neurodegeneration.59 They share a conserved CRD in the extracellular part and ECD structures of SMO and FZD2/4/5/7/8 were determined.60 However, only SMO, FZD4, and FZD5 have TMD structures.61,62,63 Lack of full-length structures and complexity in signaling pathways impeded drug discovery initiatives.60 Linking of Wnt with extracellular CRD would activate downstream signaling, while the dimerization process and the interaction between CRD and TMD remain elusive.64 It is known that the downstream effectors of Wnt signaling consist of β-catenin, planar cell polarity, and Ca2+ pathways, whereas receptor activation involves in Wnt, Norrin, FZD, LDL receptor-related protein 5/6, and many other co-factors.64 Key breakthrough is thus required to advance our knowledge of these receptors.
Agents targeting GPCRs continue to expand in the past decades. Among them, exogenous small molecules, including traditionally developed synthetic organics, natural products, and inorganics, still dominate with a total percentage of 64% (Fig. 2). Nevertheless, the proportion of small molecules declines since 2010. In addition to traditional ligand discovery, several new modalities appear, though currently at the stage of academic research. Covalent ligands, with the embedding of reactive moieties that can be covalently linked to receptors, significantly enhance the weak binding of unoptimized leads.65,66 Photoactive ligands, developed by the introduction of photo-responsive groups to drug candidates, bring a new interdisciplinary field, photopharmacology. Albeit in its infancy, it has already found in vivo applications.67,68
Analysis on agents targeting GPCRs. Distribution of molecule type (left) and action mode (right). Positive, PAM; Negative, NAM
In comparison, biologicals, such as peptides, antibodies, and metabolites, become more and more visible in the list. Particularly, the number of approved peptide drugs occupies approximately one third of the whole repertoire, with many more in different clinical stages as the pipeline41,69—most of them target classes A and B GPCRs. Naturally occurring peptides have been continually discovered from plants, animals, fungi, and bacteria. Although they act as efficient chemical messengers to modulate cellular functions, these peptides suffer from unfavorable pharmacokinetic and pharmacodynamics properties, such as very short plasma half-lives and low plasma protein binding. Therefore, chemical modifications are required to promote the membrane permeability, brain penetration, and oral bioavailability.70 Available strategies include peptide cyclization, N-methylation, palmitoylation, unnatural amino acid insertion, peptide–small molecule conjugation, and peptide self-assembly. By the way, developing peptidic agents may offer a new app
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