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Patients with cardiovascular comorbidities are more susceptible to severe infection with SARS-CoV-2, known to directly cause pathological damage to cardiovascular tissue. We outline a screening platform using human embryonic stem cell-derived cardiomyocytes, confirmed to express the protein machinery critical for SARS-CoV-2 infection, and a SARS-CoV-2 spike-pseudotyped virus system. The method has allowed us to identify benztropine and DX600 as novel inhibitors of SARS-CoV-2 infection in a clinically relevant stem cell-derived cardiomyocyte line. Discovery of new medicines will be critical for protecting the heart in patients with SARS-CoV-2, and for individuals where vaccination is contraindicated., Williams et al. confirm that human embryonic stem cell-derived cardiomyocytes express the protein machinery critical for SARS-CoV-2 infection and are susceptible to SARS-CoV-2 spike protein pseudotyped virus infection. They further use this platform as a screen to identify inhibitors of SARS-CoV-2 infection, reporting benztropine (targeting B0AT1/ACE2 complex) and DX600 (targeting ACE2) as potential inhibitors.

Acknowledgements: We thank the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) for supporting the COVID-Hep and SECURE-Liver registries; S. Marciniak and P. J. Lehner for comments and feedback on the manuscript; I. Goodfellow for providing the viral isolate; M. Wills and S. Clare for all their work ensuring a safe CL-3 working environment; C. Cormie for general lab support; the NIHR Cambridge BRC Cell Phenotyping Hub for their help with flow cytometry and processing of samples; the building staff of the Jeffrey Cheah Biomedical Centre for maintaining the institute open and safe during the period of lockdown; K. Füssel for coordinating the volunteer study and sample collection at the University Medical Centre Hamburg-Eppendorf; J. Hails, K.-I. Nikitopoulou and A. Ford for collecting blood samples; M. Colzani for advising on flow cytometry; A. Wiblin for advising on antibodies; and the Cambridge Biorepository for Translational Medicine for the provision of human tissue used in the study. T.B. was supported by an EASL Juan Rodès PhD fellowship. F.S. was supported by a UKRI Future Leaders fellowship, the Evelyn trust, an NIHR Clinical Lectureship, the Academy of Medical Sciences Starter Grant for Clinical Lecturers, the Addenbrooke’s Charitable Trust and the Rosetrees Trust. In addition, the F.S. laboratory is supported by the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre and the core support grant from the Wellcome Trust and Medical Research Council (MRC) of the Wellcome–Medical Research Council Cambridge Stem Cell Institute. The L.V. laboratory is funded by the ERC advanced grant New-Chol, the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre and the core support grant from the Wellcome Trust and MRC of the Wellcome–Medical Research Council Cambridge Stem Cell Institute. M.M., S.F. and G.D. are funded by the NIHR Cambridge Biomedical Research Centre and NIHR AMR Research Capital Funding Scheme (NIHR200640). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. V.L.M. was funded by an MRC Clinical Research Training Fellowship. G.F.M. was funded by a post-doctoral fellowship from the National Institute for Health Research (NIHR) Rare Diseases–Translational Research Collaboration (RD-TRC) and by an MRC Clinical Academic Research Partnership (CARP) award. The UK-PBC Nested Cohort study was funded by an MRC Stratified Medicine award (MR/L001489/1). C.J.R.I. was supported by the Medical Research Council (MC_UU_12014). T.M. is funded by a Wellcome Trust Clinical Research Training Fellowship (102176/B/13/Z). The A.P.D. laboratory was supported by BHF TG/18/4/33770, Wellcome Trust 203814/Z/16/A and Addenbrooke’s Charitable Trust. The COVID-Hep.net registry was supported by the European Association for the Study of the Liver (EASL) and the SECURE-Liver registry was supported by the American Association for the Study of Liver Disease (AASLD). The lung perfusion experiment was supported by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation at Newcastle University and the University of Cambridge in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the author(s) and not necessarily those of the NIHR, the Department of Health and Social Care or NHSBT. G.B. is funded by the European Reference Network for Hepatological Diseases (ERN RARE LIVER). A.O. acknowledges funding for preclinical research on treatment and prevention of COVID-19 from Unitaid (2020-38-LONGEVITY), the Engineering and Physical Sciences Research Council (EPSRC; EP/R024804/1), the Wellcome Trust (222489/Z/21/Z) and UK Research and Innovation (UKRI; BB/W010801/1). N.J.M. acknowledges funding from the MRC (CSF ref. MR/P008801/1 to N.J.M.), NHSBT (grant ref. WPA15-02 to N.J.M.) and Addenbrooke’s Charitable Trust (grant ref. to 900239 N.J.M.). This research was funded in whole, or in part, by the Wellcome Trust (203151/Z/16/Z, 203151/A/16/Z) and the UKRI Medical Research Council (MC_PC_17230). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission., Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

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. Many G protein-coupled receptors (GPCRs) have endogenous peptide agonists, and modifying the sequence of these peptides has led to some successful therapeutics. In this Review, Davenport and colleagues discuss strategies to generate effective GPCR-targeted peptide therapeutics by introducing chemical novelty, extending plasma half-life, improving a therapeutic’s drug-like properties or generating biased ligands. These approaches could overcome some of the challenges in developing peptide therapeutics.

Objective: Coronary microvascular dysfunction (CMD) can complicate successful percutaneous coronary intervention (PCI). The potent endogenous vasoconstrictor peptide Endothelin-1 (ET-1) may be an important mediator. To investigate the mechanism, we sought to define the peri-procedural trans-myocardial gradient (TMG-coronary sinus minus aortic root levels) of ET-1 and its precursor peptide - Big ET-1. We then assessed correlation with pressure-wire indices of CMD: coronary flow reserve (CFR) and index of microvascular resistance (IMR). Methods: Paired blood samples from the guide catheter and coronary sinus were collected before and after pressure-wire-guided PCI from patients with stable angina. Plasma was analysed using a specific enzyme-linked immunosorbent assay for quantification of ET-1 peptides and correlated with pressure-wire data. Non normally distributed continuous variables are presented as median [IQR]. Results: ET-1 and Big ET-1 increased post-PCI in the aorta (ET-1: 0.98 [0.76-1.26] pg/ml to 1.20 [1.03-1.67] pg/ml, P < 0.001 and Big ET-1: 2.74 [1.78-2.50] pg/ml to 3.36 [2.33-3.97] pg/ml, P < 0.001) and coronary sinus (ET-1: 1.00 [0.81-1.28] pg/ml to 1.09 [0.91-1.30] pg/ml, P = 0.03 and Big ET-1: 2.89 [1.95-3.83] pg/ml to 3.56 [2.66-4.83] pg/ml, P = 0.01). TMG of ET-1 shifted negatively compared with baseline following PCI reflecting significantly increased extraction (0.03 [-0.12-0.17] pg/ml pre-PCI versus -0.16 [-0.36-0.07] pg/ml post-PCI, P = 0.01). Increased ET-1 trans-myocardial extraction correlated with higher IMR (Pearson's r = 0.293, P = 0.02) and increased hyperemic transit time (Pearson's r = 0.333, P < 0.01). In subgroup analysis, mean ET-1 trans-myocardial extraction was higher amongst patients with high IMR compared with low IMR (0.73 pg/ml, SD:0.78 versus 0.17 pg/ml, SD:0.42, P = 0.02). There was additionally a numerical trend towards increased ET-1 trans-myocardial extraction in subgroups of patients with low CFR and in patients with Type 4a Myocardial Infarction, albeit not reaching statistical significance. Conclusions: Circulating ET-1 increases post-PCI and upregulated ET-1 trans-myocardial extraction contributes to increased microcirculatory resistance.

Aims The apelin receptor, a G protein-coupled receptor, has emerged as a key regulator of cardiovascular development, physiology, and disease. However, there is a lack of suitable human in vitro models to investigate the apelinergic system in cardiovascular cell types. For the first time we have used human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and a novel inducible knockdown system to examine the role of the apelin receptor in both cardiomyocyte development and to determine the consequences of loss of apelin receptor function as a model of disease. Methods and results Expression of the apelin receptor and its ligands in hESCs and hESC-CMs was determined. hESCs carrying a tetracycline-inducible short hairpin RNA targeting the apelin receptor were generated using the sOPTiKD system. Phenotypic assays characterized the consequences of either apelin receptor knockdown before hESC-CM differentiation (early knockdown) or in 3D engineered heart tissues as a disease model (late knockdown). hESC-CMs expressed the apelin signalling system at a similar level to the adult heart. Early apelin receptor knockdown decreased cardiomyocyte differentiation efficiency and prolonged voltage sensing, associated with asynchronous contraction. Late apelin receptor knockdown had detrimental consequences on 3D engineered heart tissue contractile properties, decreasing contractility and increasing stiffness. Conclusions We have successfully knocked down the apelin receptor, using an inducible system, to demonstrate a key role in hESC-CM differentiation. Knockdown in 3D engineered heart tissues recapitulated the phenotype of apelin receptor down-regulation in a failing heart, providing a potential platform for modelling heart failure and testing novel therapeutic strategies.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. The mainstay of treatment for CKD is blockade of the renin–angiotensin–aldosterone system (RAAS), which reduces blood pressure and proteinuria and slows kidney function decline. Despite this treatment, many patients progress to kidney failure, which requires dialysis or kidney transplantation, and/or die as a result of cardiovascular disease. The apelin system is an endogenous physiological regulator that is emerging as a potential therapeutic target for many diseases. This system comprises the apelin receptor and its two families of endogenous ligands, apelin and elabela/toddler. Preclinical and clinical studies show that apelin receptor ligands are endothelium-dependent vasodilators and potent inotropes, and the apelin system has a reciprocal relationship with the RAAS. In preclinical studies, apelin regulates glomerular haemodynamics and acts on the tubule to promote aquaresis. In addition, apelin is protective in several kidney injury models. Although the apelin system has not yet been studied in patients with CKD, the available data suggest that apelin is a promising potential therapeutic target for kidney disease., The apelin system is a broad regulator of physiology that has beneficial cardiovascular and renal effects. This Review focuses on the role of this system in kidney and cardiovascular health and disease and its potential as a therapeutic target., Key points Chronic kidney disease (CKD) is common worldwide and is associated with high cardiovascular morbidity and mortality; however, treatment options are limited.The apelin system is a broad regulator of physiology that opposes the renin–angiotensin–aldosterone system (RAAS) and has beneficial cardiovascular effects in health and disease.Increasing evidence indicates that apelin has favourable effects on renal physiology, including roles in the regulation of fluid balance and glomerular haemodynamics.Preclinical models demonstrate direct anti-inflammatory and anti-fibrotic actions of the apelin system in models of kidney injury; targeting the apelin receptor in combination with RAAS blockers might offer synergistic benefits.The apelin system is an attractive potential therapeutic target for CKD, offering direct renal protection in addition to targeting the associated cardiovascular complications.

[Pyr1]apelin-13 is the predominant apelin peptide isoform in the human cardiovascular system and plasma. To date, few studies have investigated [Pyr1]apelin-13 metabolism in vivo in rats with no studies examining its stability in humans. We therefore aimed to develop an LC-MS/MS method for detection and quantification of intact [Pyr1]apelin-13 and have used this method to identify the metabolites generated in vivo in humans. [Pyr1]apelin-13 (135 nmol/min) was infused into six healthy human volunteers for 120 minutes and blood collected at time 0 and 120 minutes after infusion. Plasma was extracted in the presence of guanidine hydrochloride and analysed by LC-MS/MS. Here we report a highly sensitive, robust and reproducible method for quantification of intact [Pyr1]apelin-13 and its metabolites in human plasma. Using this method, we showed that the circulating concentration of intact peptide was 58.3 ± 10.5 ng/ml after 120 minutes infusion. We demonstrated for the first time that in humans, [Pyr1]apelin-13 was cleaved from both termini but the C-terminal was more susceptible to cleavage. Consequently, of the metabolites identified, [Pyr1]apelin-13(1–12), [Pyr1]apelin-13(1–10) and [Pyr1]apelin-13(1–6) were the most abundant. These data suggest that apelin peptides designed for use as cardiovascular therapeutics, should include modifications that minimise C-terminal cleavage.

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and, in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targeting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed, an agenda for drug repurposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methods aimed at discovering novel chemical and biological means of targeting a short list of host and viral entities which should extend the arsenal of anti-SARS-CoV-2 agents. This longer term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

[Pyr1]apelin-13 is the predominant apelin peptide isoform in the human cardiovascular system and plasma. To date, few studies have investigated [Pyr1]apelin-13 metabolism in vivo in rats with no studies examining its stability in humans. We therefore aimed to develop an LC-MS/MS method for detection and quantification of intact [Pyr1]apelin-13 and have used this method to identify the metabolites generated in vivo in humans. [Pyr1]apelin-13 (135 nmol/min) was infused into six healthy human volunteers for 120 minutes and blood collected at time 0 and 120 minutes after infusion. Plasma was extracted in the presence of guanidine hydrochloride and analysed by LC-MS/MS. Here we report a highly sensitive, robust and reproducible method for quantification of intact [Pyr1]apelin-13 and its metabolites in human plasma. Using this method, we showed that the circulating concentration of intact peptide was 58.3 ± 10.5 ng/ml after 120 minutes infusion. We demonstrated for the first time that in humans, [Pyr1]apelin-13 was cleaved from both termini but the C-terminal was more susceptible to cleavage. Consequently, of the metabolites identified, [Pyr1]apelin-13(1–12), [Pyr1]apelin-13(1–10) and [Pyr1]apelin-13(1–6) were the most abundant. These data suggest that apelin peptides designed for use as cardiovascular therapeutics, should include modifications that minimise C-terminal cleavage.

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14747. In addition to this overview, in which are identified Other protein targets which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.