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Advances in Therapeutic Peptides Targeting G Protein-Coupled Receptors

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Advances in Therapeutic Peptides Targeting G Protein-Coupled Receptors REVIEWS Advances in therapeutic peptides targeting G protein- coupled receptors Anthony P. Davenport 1,3 ✉ , Conor C. G. Scully2,3, Chris de Graaf2, Alastair J. H. Brown2 and Janet J. Maguire 1 Abstract | Dysregulation of peptide- activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) — nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology , and more than 10 potentially first- in- class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide- binding GPCRs. Increasingly , novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug- like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties. G protein- coupled receptors (GPCRs) mediate a wide A further 87 ‘orphan’ receptors from different families range of signalling processes and are targeted by one — for which the endogenous ligand is not yet known — third of the drugs in clinical use1. Although most have been identified in the human genome. In the cases GPCR- targeting therapeutics are small molecules2, of 54 of these orphans, at least one publication has pro- the endogenous ligands for many GPCRs are peptides posed an endogenous ligand, and some of these ligands (comprising 50 or fewer amino acids), which suggests are peptides4. The ‘de- orphanization’ of these receptors that this class of molecule could be therapeutically is ongoing. For example, G protein-coupled receptor 171 useful. (GPR171) and GPR83 were recently found to interact GPCRs are divided into families based on structural with the neuropeptides PEN and LEN, respectively, similarities. The largest group is the class A (rhodopsin- which are abundant in mouse brain (and highly con- like) family, followed by the class B (secretin) family. served in humans). Initial studies suggest that these Although other families exist, including class C and the GPCRs may be functionally coupled in the regulation frizzled and adhesion classes, therapeutics have predom- of feeding, and if substantiated, the receptors could be inantly targeted class A and B GPCRs, so this Review is new potential drug targets5,6. focused on these two groups. The International Union Endogenous peptides that bind to GPCRs on cell sur- of Basic and Clinical Pharmacology (IUPHAR) Guide faces spatiotemporally span paracrine and autocrine sig- 1Experimental Medicine 3 and Immunotherapeutics, to Pharmacology currently lists 197 class A receptors nalling, from long- acting hormones to locally released Addenbrooke’s Hospital, with known ligands (excluding olfactory, vision, taste mediators of cellular functions and neurotransmitters. University of Cambridge, and vomeronasal sensory receptors), where 64 (32%) of Peptides are one of the largest and most ancient classes Cambridge, UK. these bind to endogenous peptides3. In GPCR class B, of intercellular chemical messengers7. The pioneering 2Sosei Heptares, Granta Park, there are 20 receptors activated by 15 endogenous development, using these naturally occurring peptides as Cambridge, UK. peptides. These GPCRs are grouped in the following therapeutics, was the use of insulin in the 1920s. Insulin 3 These authors contributed families, based on the ligand to which they bind: calci- principally targets a tyrosine kinase receptor8, and the equally: A. P. Davenport, C. C. G. Scully. tonin, corticotropin-releasing factor, glucagon, para- development of this therapeutic exploited the remark- ✉e- mail: apd10@ thyroid hormone (which is generally considered to able pharmacodynamic properties of peptides: their high medschl.cam.ac.uk be a peptide, despite its 84-amino-acid length), vaso- affinity, selectivity and potency. In line with the observed https://doi.org/10.1038/ active intestinal peptide (VIP) or pituitary adenylate effects of insulin, most other peptide therapies are well s41573-020-0062- z cyclase-activating peptide (PACAP). tolerated, with few off-target effects. NATURE REVIEWS | DRUG DISCOVERY VOLUME 19 | JUNE 2020 | 389 REVIEWS Cryo- electron microscopy Naturally occurring peptides, however, do not typ- increases in plasma half- life) and pharmacodynamics (cryo-​EM). Electron microscopy ically make good therapeutics. The development of (via increased potency), as well as ligand bias. technique that allows peptides as drugs has been limited by poor pharmaco- near- atomic resolution kinetics (short half- life, rapid degradation and high Approved peptide therapeutics of biomolecules such as G protein- coupled receptors levels of clearance) and by a lack of oral bioavailability The majority of GPCR- targeting peptide drugs that (GPCRs) in samples cooled due to a combination of low gastrointestinal stability and are either approved for clinical use or in development to low temperatures and poor permeability. Therefore, strategies need to be devel- function as agonists and are used to replace or enhance embedded in an environment oped that can address these aspects before most peptides low levels of endogenous peptides. In class A, the major of vitreous water, avoiding can become effective medicines. receptor targets include μ and κ opioid receptors (abbre- the crystallization that is a prerequisite for X- ray Peptide drugs occupy a structural space between viated MOR and KOR, respectively) to relieve pain; crystallography. biologics (antibodies and proteins) and small molecules. oxytocin and vasopressin receptors for the induction of Whereas endogenous signalling peptides usually have labour; and apelin and angiotensin receptors in cardio- 50 or fewer residues, the FDA defines peptide drugs9 as vascular disease (TABLES 1,2). More specialized targets having a maximum of 40 residues (a few exceptions have include the somatostatin receptor, for acromegaly and been noted), not limited to the 20 genetically encoded Cushing’s disease. Peptide therapies that target class B amino acids. These therapeutics are undergoing a renais- receptors are dominated by GLP-1 receptor agonists sance. Emerging novel strategies include half- life exten- for the treatment of type 2 diabetes mellitus (T2D), sion platforms, stapling and resistance to proteolysis, along with synthetic or modified versions of peptide all of which significantly improve pharmacokinetics hormones. and oral bioavailability. These strategies are perhaps Few antagonists have made it to the clinic. Most of best exemplified by the development of glucagon- like those that have made this leap target class A GPCRs. peptide 1 (GLP-1) receptor agonists that have increased Antagonists that block the action of gonadotrophin- resistance to proteolytic degradation and reduced renal releasing hormone, such as degarelix and abarelix, or clearance. Several successfully marketed products and a agonists that desensitize the receptor in order to have the multitude of preclinical novel approaches (for example, same effect, such as buserelin, are used for the treatment stapling, cyclization and glycosylation) have come from of cancer. these efforts. This success has also fostered the develop- ment of multifunctional peptides that combine agonism Synthetic endogenous peptide analogues for two or more GPCRs in the same peptide, based on Oxytocin12,13 and vasopressin were the first chemically relatively high sequence homology and similar bind- synthesized variants of endogenous peptides for class A ing sites. Complementary pharmacodynamic strate- receptors to enter clinical use, and they did so in the gies are extending the repertoire of drugs that act at a 1950s. These two peptides are amongst the ten peptides given GPCR. that are usually synthesized chemically or by recom- Peptide ligands are also emerging that can selectively binant technology but that have sequences identical activate downstream signalling pathways — for exam- to those of their endogenous peptide equivalents, and ple, G proteins or β- arrestins (the two main pathways that have been approved for clinical use in one or more downstream of GPCRs) — towards which these ligands countries (Table 1). Evaluation of those ten peptides pro- are described as being biased. These pathways may be vides an opportunity to examine the properties of native linked to distinct physiological or pathophysiological peptides that may limit or enable their widespread thera- responses, either beneficial or detrimental, so biased peutic application, as well as to investigate the impact of ligands can, in theory, be designed to have the optimum those properties on drug development strategies. therapeutic activity, but with reduced side effects or The peptides that target class A GPCRs are mainly receptor internalization. agonists that bind with both high affinity (median neg- The application of structure-based design has signifi- ative log of the dissociation constant (pKi) = 8.4) and cantly altered all aspects of small-molecule drug discov- potency
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