Mini Reviews in Medicinal Chemistry - Volume 12, Issue 9, 2012

The protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) that are uniquely activated by proteolysis. PARs mediate hemostasis, thrombosis, inflammation, embryonic development and progression of certain malignant cancers. The family of PARs include four members: PAR1, PAR2, PAR3 and PAR4. PARs harbor a cryptic ligand sequence within their N-terminus that is exposed following proteolytic cleavage. The newly formed PAR Nterminus functions as a tethered ligand that binds intramolecularly to the receptor to trigger transmembrane signaling. This unique mechanism of activation would indicate that regardless of the activating protease, cleavage of PARs would unmask a tethered ligand sequence that would induce a similar active receptor conformation and signaling response. However, this is not the case. Recent studies demonstrate that PARs can be differentially activated by synthetic peptide agonists, proteases or through dimerization, that ultimately result in distinct cellular responses. In some cases, allosteric modulation of PARs involves compartmentalization in caveolae, plasma membrane microdomains enriched in cholesterol. Here, we discuss some mechanisms that lead to allosteric modulation of PAR signaling.

G protein-coupled receptors (GPCRs) can be activated by multiple ligands and exhibit the capacity to couple to numerous intracellular signal transduction pathways. This property allows GPCRs to be modulated by biased agonists that selectively activate specific subsets of GPCR-regulated cellular signaling proteins. The angiotensin II type 1 receptor (AT1R) is a GPCR that endogenously binds to the peptide ligand angiotensin II. More recently it has been demonstrated that a modified peptide, [Sar1I-le4-Ile8]-angiotensin II (SII) acts as a biased agonist towards the AT1R. SII binds to the AT1R without promoting heterotrimeric G protein-coupling, but serves to link the receptor to the beta-arrestin-dependent activation of the mitogen activated protein kinase pathway. The present mini-review summarizes current knowledge regarding the role of biased agonists in stimulating biased AT1R signaling.

The great versatility of G protein-coupled receptors (GPCRs), in terms of both their ability to bind different types of ligands and initiate a large number of distinct cellular signaling events, remains incompletely understood. In recent years, the classical view of the nature and consequences of ligand binding to GPCRs has dramatically changed. The notion of functional selectivity, achieved through both biased ligands and allosteric modulators, has brought substantial new insight into our comprehension of the pluridimensionality of signaling achieved by GPCRs. Moreover, receptor heterodimerization adds another important dimension to the diversity of cellular responses controlled by GPCRs. Here, we review these considerations and discuss how they will impact the design of improved therapeutics.

Pharmacotherapeutic targeting of G protein-coupled receptors (GPCRs) is perhaps the most important field of drug design, as agents designed to control these receptors constitute more than half of the pharmacopeia. Initially GPCRs were considered to be unitary entities, possessing all of their potential functionality in their characteristic heptahelical core. Early models of the functional activity of GPCRs considered them to possess just a simple ‘on’ or ‘off’ status. Recent research however has allowed us to realize that GPCR functionality is dependent upon many other proteins outside of the heptahelical core, on the site of GPCR expression in a tissue or a microdomain in a cell, and, most importantly, on the formation of differential ‘active’ states preferentially coupled to specific signal transduction structures. The recognition of such signaling diversity has facilitated the ability to appreciate and identify ligands for GPCRs that demonstrate a bias towards one signaling form of a receptor to another. However while potentially increasing our ability for selective signal targeting, our approach to understanding the physiological ramifications of systemic signaling manipulation is underdeveloped. This explosion in the complexity of GPCR signaling is now becoming familiar territory to receptor biologists, yet the application of this knowledge to drug design is relatively limited. This review will attempt to outline potential pitfalls and unseen benefits of using signaling bias in therapeutic design as well as highlighting new applications such as Game Theory for uncovering new therapeutic applications for biased agonists.

Gonadotropin-releasing hormone is a neuropeptide that acts via Gq coupled G-protein coupled receptors in the pituitary that mediate central control of reproduction. GnRH receptors (GnRHR) and GnRH ligands are also found in extra-pituitary sites including the CNS as well as reproductive tissues and cancer cells derived from such tissues. Much of the interest in the extra-pituitary receptors stems from the fact that they mediate anti-proliferative and/or pro-apoptotic effects and may therefore be directly targeted for cancer therapy. Type I mammalian GnRHR are atypical in that they do not bind to (or signal via) arrestins. In spite of this restriction on their signaling repertoire, there is good evidence for existence of multiple active GnRHR conformations and for activation of multiple upstream effectors (heterotrimeric and monomeric G-proteins). In this review GnRHR signaling is described, with emphasis on the relevance of functional selectivity for pharmacological characterization of GnRHR ligands, as well as its possible contribution to contextdependent GnRHR signaling and relevance for GnRHR-mediated effects on cell fate as well as GnRHR trafficking.

G protein-coupled receptors (GPCRs) can couple to more than one signaling pathway. Biophysical studies and pharmacological theory indicate that they exist in different active conformations that differ in their capacity to activate specific signaling pathways. Individual agonists stabilize particular active conformations and thereby can differ in their relative activation of different signaling pathways coupled to the same receptor, a phenomenon referred to as functional selectivity. Many pairs of GPCRs have been shown to interact and form heterocomplexes in vitro and in vivo. Recent studies implicate these complexes in the responses to some therapeutic drugs and drugs of abuse, and raise the possibility that they may be involved in mediating functional selectivity.

‘Biased agonism’ refers to the ability of a ligand to selectively recruit different intracellular signaling proteins to elicit distinct phenotypic effects in cells. While conventional G protein-coupled receptor (GPCR) agonism and antagonism can be regarded as modulating the quantity of efficacy, functionally selective or ‘biased’ ligands qualitatively change the trafficking of information flowing across the plasma membrane. The concept of ligand directed signaling fundamentally raises the potential of pharmacologic agents with novel therapeutic profiles possessing improved therapeutic efficacy or reduced side effects. Currently, there is little experimental evidence that biased ligands offer advantages over conventional agonists/antagonists in vivo. Recent work examining biased agonism at the type I parathyroid hormone receptor (PTH1R) demonstrates that selective activation of G protein-independent arrestin-mediated signaling pathways elicits a physiologic response in bone distinct from that induced by the conventional PTH1R agonist PTH(1-34). While intermittent (daily) administration of PTH(1-34) (teriparitide) is effective in increasing bone formation, PTH(1-34) administration is also associated with increases in bone resorption and a propensity to promote hypercalcemia/hypercalcuria. In contrast, D-Trp12,Tyr34-bPTH(7-34) (PTH-βarr), an arrestin pathway-selective agonist for the PTH1R, induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. Unlike PTH(1-34), PTH-βarr appears to ‘uncouple’ the anabolic effects of PTH1R activation from its catabolic and calcitropic effects. Such findings offer evidence that arrestin pathway-selective GPCR agonists can elicit potentially beneficial effects in vivo that cannot be achieved using conventional agonist or antagonist ligands.

Quinolones and its derivatives comprise an important group of heterocyclic compounds that exhibit a wide range of pharmacological properties such as antibacterial, antitumor, antiviral, anti-ischemic, antiparasitic and anxiolytic. Persistent efforts have been made over the years to develop novel congeners with superior biological activities and minimal potential for undesirable side-effects. The present review aims to highlight some recent discoveries on the development of novel quinolone-based compounds with potential antitubercular and anticancer activity.

HIV-1 integrase (IN) is a crucial enzyme in the life cycle of HIV-1 and also a validated target for developing anti-HIV inhibitors. Recent progress in drug design has significantly accelerated the development of anti-AIDS IN inhibitors. A large amount of novel inhibitors that interact specifically with IN were developed along with the expanding and application of methods to drug design. This article reviewed the anti-HIV IN inhibitors discovered by the rational drug design approaches in the recent 5-year.

Concurrent infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients positive for human immunodeficiency virus (HIV) is relatively common. The treatment of co-infected individuals is rather complex because the anti-viral therapy may be associated with drug-resistance, hepatotoxicity and lack of response. Herein, we present a summary of the available compounds and the recent recommendations concerning the therapeutic management of HIV/HBV and HIV/HCV co-infections.