Update on apelin peptides as putative targets for cardiovascular drug discovery

Introduction: The physiological importance of GPCR/ligand pathways is highlighted by the fact that numerous pathologies are attributed to their signaling dysfunction. Over 50% of the pharmaceutical drugs currently used to treat human disease are based on compounds that interact with GPCRs. Apelin/APJ constitutes a novel endogenous peptide/GPCR system proposed to be involved in a wide range of physiological functions. Early evidence suggests that apelin/APJ may hold promise as a target for development of novel therapeutic agents which may counteract a number of pathologies including cardiovascular disease. Despite advances in treatment of cardiovascular disease, incidence, prevalence, morbidity and economic costs remain high necessitating the development of new treatment paradigms.

Areas covered: This review summarizes apelin/APJ structure, distribution and regulation; presents evidence for a role of apelin in pressure/volume homeostasis and in the pathophysiology of cardiovascular disease; summarizes data on beneficial effects of apelin in preclinical, animal models of cardiovascular disease and measurement of plasma levels of apelin across the full spectrum of cardiovascular disease in humans; and notes the first studies describing bioactivity of apelin peptides in human healthy volunteers and patients with heart failure.

Expert opinion: More clarity is needed on the precise physiological/pathophysiological role of the apelin/APJ system in human health and disease. Nonetheless, preclinical studies and initial studies in humans show that APJ antagonism may represent a novel therapeutic target for patients with cardiovascular disease. Development of appropriately validated assays for apelin will clarify circulating levels of the peptide in health and disease. Development of suitable agonists/antagonists will pave the way for much needed future studies essential for advancing this promising field of drug discovery.     

Aquaporins as targets for drug discovery

The intracellular hydric balance is an essential process of mammalian cells. The water movement across cell membranes is driven by osmotic and hydrostatic forces and the speed of this process is dependent on the presence of specific aquaporin water channels. Since the molecular identification of the first water channel, AQP1, by Peter Agre's group, 13 homologous members have been found in mammals with varying degree of homology. The fundamental importance of these proteins in all living cells is suggested by their genetic conservation in eukaryotic organisms through plants to mammals. A number of recent studies have revealed the importance of mammalian AQPs in both physiology and pathophysiology and have suggested that pharmacological modulation of aquaporins expression and activity may provide new tools for the treatment of variety of human disorders, such as brain edema, glaucoma, tumour growth, congestive heart failure and obesity in which water and small solute transport may be involved. This review will highlight the physiological role and the pathological involvement of AQPs in mammals and the potential use of some recent therapeutic approaches, such as RNAi and immunotherapy, for AQP-related diseases. Furthermore, strategies that can be developed for the discovery of selective AQP-drugs will be introduced and discussed.     

Aquaporins as targets for drug discovery

Over the past decade, significant advances have been made in understanding how water moves in to and out of cells. Investigators have used molecular and structural biological techniques to show that nature has evolved specialized water-conducting proteins called aquaporins, which traverse biological membranes in the cells of animals, plants and even bacteria. It is becoming increasingly clear that these aquaporins have fundamental roles in normal human physiology and pathophysiology. Consequently, aquaporins are attractive targets for the development of novel drug therapies for disorders that involve aberrant water movement, such as edema and kidney disease.     

Hypothalamic peptides as drug targets for obesity

The importance of the melanocortin system in obesity has been confirmed by the recent discovery of mutations in the melanocortin MC4 receptor in morbidly obese patients and the finding that intranasal administration of a fragment of melanocortin decreases body fat in humans. Transgenic mice overexpressing melanin-concentrating hormone (MCH) are obese and a second MCH receptor has been identified. In addition, ghrelin, endocannabinoids and glucagon-like peptide 2 have been identified as potentially important central regulators of food intake.     

Adenosine receptors as targets for drug discovery.

This symposium was held on March 30, 1998 as part of the 215th American Chemical Society National Meeting. It was presided by PR McGuirk of Pfizer and was particularly aimed at medicinal chemists. There were more than 200 attendees at the symposium.     

Thrombin receptors as drug discovery targets

Summary A G-protein-coupled thrombin receptor has been identified, cloned and shown to be present on platelets, endothelial cells, fibroblasts and vascular smooth muscle cells. -Thrombin binds to this receptor via thrombin's anion-binding exosite and catalyzes exposure of a new NH₂-terminus. The new receptor NH₂-terminus acts as an agonistic tethered ligand that comprises part of the receptor it activates. The first five or more amino acids of the new NH₂-terminus (beginning with SFLLR in the human receptor) can directly activate the receptor in the absence of thrombin. Because thrombin receptor activation may participate in thrombosis, inflammation and fibroproliferative disorders, research is being conducted on several strategies that might interfere with the receptor-mediated pathophysiologic actions of thrombin. The structure-activity relationship for thrombin receptor agonist peptides has been studied in detail, and some general requirements for agonist activity have emerged. Although several peptide-based thrombin receptor antagonists have been described, these earliest examples are not very potent and they appear to be partial agonists in cells other than platelets. Despite the limitations of these prototypes, initial studies with such compounds have demonstrated the importance of this thrombin receptor in -thrombin-mediated activation of platelets and certain other cells and in arterial thrombosis.     

CART peptides as targets for CNS drug development

CART peptides are relatively novel neuropeptides involved in feeding, drug reward and stress. They are formed from a proCART polypeptide that is 89 amino acids in length in the human version. Fragments 42-89 and 49-89 are behaviorally active in feeding and locomotion as well and other functions. These peptides are highly abundant and widely but discretely distributed in the brain, gut, pituitary, adrenals and pancreas. The presence of CART immunoreactivity in specific nuclei of the hypothalamus has led to an examination of icv-injected CART peptides effects on feeding, which have proven to be significantly anorectic. Studies of transgenic animals and humans have also demonstrated a linkage to both obesity and anorexia. Similarly, the localization of CART to sub-regions of the mesolimbic dopamine system has led to demonstration of the effects of CART peptides on locomotor activity and conditioned place preference when injected into the ventral tegmental area (VTA), which are psychostimulant-like in quality. These findings also suggest that CART has the capacity to modulate mesolimbic dopamine, which could have implications for the treatment not only of psychostimulant abuse but also for the treatment of other disorders with mesolimbic dopamine involvement, such as schizophrenia. Other lines of evidence also show that CART peptides are involved in fear and startle behaviors which may have implications for understanding anxiety and stress. An important part of the development of CART mimetics and related drugs would be the identification of CART receptors. At the present time such receptors have not been identified, and much effort should be directed at this problem. Nonetheless, CART peptides offer interesting targets for new drug development for obesity and, potentially, a number of other disorders.     

Endogenous kynurenines as targets for drug discovery and development

The kynurenine pathway is the main pathway for tryptophan metabolism. It generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The pathway is in a unique position to regulate other aspects of the metabolism of tryptophan to neuroactive compounds, and also seems to be a key factor in the communication between the nervous and immune systems. It also has potentially important roles in the regulation of cell proliferation and tissue function in the periphery. As a result, the pathway presents a multitude of potential sites for drug discovery in neuroscience, oncology and visceral pathology.     

HIV-1 assembly and budding as targets for drug discovery

Research conducted during the past several years has led to an increased understanding of the roles played by the viral protein Gag and specific cellular factors in HIV assembly/budding. The identification of compounds that interfere with this process validates this late step in virus replication as a target for HIV therapeutic discovery. In this review, current understanding of HIV-1 assembly/budding is described and several developmental stage drugs that target this process are reviewed.     

TACE and other ADAM proteases as targets for drug discovery

Tumor necrosis factor (TNF)-converting enzyme (TACE) and other ADAM proteases (those that contain a disintegrin and a metalloprotease domain) have emerged as potential therapeutic targets in the areas of arthritis, cancer, diabetes and HIV cachexia. TACE is the first ADAM protease to process the known physiological substrate and inflammatory cytokine, membrane-bound precursor-TNF-alpha, to its mature soluble form. Subsequently, TACE was shown to be required for several different processing events such as tumor growth factor-alpha (TGF-alpha) precursor and amyloid precursor protein (APP) cleavage. With the recent discoveries of the proteolytic specificities of other ADAM family members, the information surrounding these metalloproteases is expanding at an exponential rate. This review focuses on TACE and other family members with known proteolytic function as well as the inhibitors of this class of enzyme.     

Bacterial DNA replication enzymes as targets for antibacterial drug discovery

Introduction: The bacterial replisome is composed of a large number of enzymes, which work in exquisite coordination to accomplish chromosomal replication. Effective inhibition inside the bacterial cell of any of the ‘essential’ enzymes of the DNA replication pathway should be detrimental to cell survival.

Areas covered: This review covers DNA replication enzymes that have been shown to have a potential for delivering antibacterial compounds or drug candidates including: type II topoisomerases, a clinically validated target family, and DNA ligase, which has yielded inhibitors with in vivo efficacy. A few of the ‘replisome’ enzymes that are structurally and functionally well characterized and have been subjects of antibacterial discovery efforts are also discussed.

Expert opinion: Identification of several essential genes in the bacterial replication pathway raised hopes that targeting these gene products would lead to novel antibacterials. However, none of these novel, single gene targets have delivered antibacterial drug candidates into clinical trials. This lack of productivity may be due to the target properties and inhibitor identification approaches employed. For DNA primase, DNA helicase and other replisome targets, with the exception of DNA ligase, the exploitation of structure for lead generation has not been tested to the same extent that it has for DNA gyrase. Utilization of structural information should be considered to augment HTS efforts and initiate fragment-based lead generation. The complex protein–protein interactions involved in regulation of replication may explain why biochemical approaches have been less productive for some replisome targets than more independently functioning targets such as DNA ligase or DNA gyrase.     

Brain neuronal nicotinic receptors as new targets for drug discovery

Neuronal nicotinic receptors (nAChRs) are a heterogeneous family of ion channels differently expressed in the nervous system where, by responding to the endogenous neurotransmitter acetylcholine, they contribute to a wide range of brain activities and influence a number of physiological functions. Over recent years, the application of newly developed molecular and cellular biological techniques has made it possible to correlate the subunit composition of nAChRs with specific nicotine-elicited behaviours, and refine some of the in vivo physiological functions of nAChR subtypes. The major new findings are the widespread expression of nAChRs, outside the nervous system, their specific and complex organisation, and their relevance to normal brain function. Moreover, the combination of clinical and basic research has better defined the involvement of nAChRs in a growing number of nervous pathologies other than degenerative diseases. However, there are still only a limited number of nicotinic-specific drugs and, although some nicotinic agonists have an interesting pharmacology, their clinical use is limited by undesirable side effects. Some selective nicotinic ligands have recently been developed and used to explore the complexity of nAChR subtype structure and function in the expectation that they will become rational therapeutic alternatives in a number of neurodegenerative, neuropsychiatric and neurological disorders. In this review, we will discuss the molecular basis of brain nAChR structural and functional diversity mainly in pharmacological and biochemical terms, and summarise current knowledge concerning the newly discovered drugs used to classify the numerous receptor subtypes and treat the brain diseases in which nAChRs are involved.     

Bacterial DNA replication enzymes as targets for antibacterial drug discovery

INTRODUCTION: The bacterial replisome is composed of a large number of enzymes, which work in exquisite coordination to accomplish chromosomal replication. Effective inhibition inside the bacterial cell of any of the 'essential' enzymes of the DNA replication pathway should be detrimental to cell survival. AREAS COVERED: This review covers DNA replication enzymes that have been shown to have a potential for delivering antibacterial compounds or drug candidates including: type II topoisomerases, a clinically validated target family, and DNA ligase, which has yielded inhibitors with in vivo efficacy. A few of the 'replisome' enzymes that are structurally and functionally well characterized and have been subjects of antibacterial discovery efforts are also discussed. EXPERT OPINION: Identification of several essential genes in the bacterial replication pathway raised hopes that targeting these gene products would lead to novel antibacterials. However, none of these novel, single gene targets have delivered antibacterial drug candidates into clinical trials. This lack of productivity may be due to the target properties and inhibitor identification approaches employed. For DNA primase, DNA helicase and other replisome targets, with the exception of DNA ligase, the exploitation of structure for lead generation has not been tested to the same extent that it has for DNA gyrase. Utilization of structural information should be considered to augment HTS efforts and initiate fragment-based lead generation. The complex protein-protein interactions involved in regulation of replication may explain why biochemical approaches have been less productive for some replisome targets than more independently functioning targets such as DNA ligase or DNA gyrase.