Sunanda G. Dastidar

Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT1 and CysLT2. The CysLT1 receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT2 receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT1-receptor-mediated effects, and the role of the CysLT2 receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT2-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.

Cysteine cathepsin S as an immunomodulatory target: present and future trends.

Objective: Antigen presentation is the key to immune response. Cathepsin S plays a major role in the degradation of the invariant peptide chain associated with the major histocompatibility complex and thus affects antigen presentation. This review will focus on the recent developments made in field of cysteine cathepsins especially cathepsin S and their future prospects as a therapeutic target. Methods: Selective cathepsin inhibitors for targeting autoimmune disorders, atherosclerosis, osteoporosis, osteoarthritis and cancer are being pursued by many pharmaceutical companies. Recent publications in this field have been used as references to evaluate the current and future trends in cathepsin S inhibitors as an immunomodulatory target. Conclusions: The temporal and spatial position occupied by cathepsin S in immune presentation, gives rise to the hope that an inhibitor would impart selectivity with a lesser propensity for side effects than other immunosuppressive agents.

Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics

Importance of the field: The Polo-like kinase (Plk) family has emerged as an important regulator in cell cycle progression. Plks belong to a family of serine/threonine kinases and exist in four isoforms Plk1- 4. However, only one of these isoforms, Plk1, is shown to be involved in the activation of Cdc2, chromosome segregation, centrosome maturation, bipolar spindle formation and execution of cytokinesis. The activity of Plk1 is elevated in tissues and cells with a high mitotic index. In patients, Plk1 is overexpressed in tumors including those derived from lung, breast, colon, pancreas, prostate and ovary. Plk1 depletion is associated with the decrease in cell viability and induction of apoptosis in various cancerous cells. Several Plk1 inhibitors are in different phases of clinical development for anticancer therapy. Areas covered in this review: The focus of present review is to highlight Plk1 as a promising therapeutic approach for the treatment of cancer. The review discusses the role of Plk1 in cancer and the current status of Plk1 inhibitors, as well as highlighting the possible beneficial effect of inhibition of Plk1 as compared to other mitotic targets. What the reader will gain: Readers will get a comprehensive overview of Plk1 as a novel anticancer drug target. This review will also update readers about the progress made in the field of Plk1 inhibitors. Take home message: The current literature about Plk1 inhibitors and knockout studies favor Plk1 inhibition as a potential antitumor therapy.

Spleen tyrosine kinase: a novel target for therapeutic intervention of rheumatoid arthritis

Background: In the last few years, significant progress has been made in understanding the pathogenic mechanisms and in defining the role of relevant cells and molecules in the pathophysiology of rheumatoid arthritis (RA). Various therapies, both biological (anti-TNF, anti-interleukins [e.g., IL-1]) and small molecule inhibitors have been explored for the treatment of RA. Objective: To date, no single signaling pathway inhibitor as wide acting as the corticosteroids, is known. However, treatment with corticosteroids is also associated with allied side effects. Despite a lot of efforts in the category of small molecule inhibitors, no inhibitor is available to deal with RA at both fronts (inflammation and tissue damage), without causing immense side effects. Method: This present review explores the role of spleen tyrosine kinase (Syk) in the pathogenesis of RA and also discusses how it may meet the present day therapeutic requirements for the treatment of RA. This review gives an in-depth discussion on the role of Syk signaling in RA, the possibilities of using Syk as a target and also discusses the possible side effects that could be associated with its inhibition. Conclusion: We propose Syk inhibition as a potential therapeutic approach for the treatment of RA.

A review on leukotrienes and their receptors with reference to asthma

Abstract Objective and methods: Leukotrienes (LTs) including cysteinyl leukotrienes (CysLTs) and LTB4 are the most potent inflammatory lipid mediators and play a central role in the pathophysiology of asthma and other inflammatory diseases. These biological molecules mediate a plethora of contractile and inflammatory responses through specific interaction with distinct G protein-coupled receptors (GPCRs). The main objective of this review is to present an overview of the biological effects of CysLTs and their receptors, along with the current knowledge of mechanisms and role of LTs in the pathogenesis of asthma. Results: CysLTs including LTC4, LTD4 and LTE4 are ligands for CysLT1 and CysLT2 receptors, and LTB4 is the agonist for BLT1 and BLT2 receptors. The role of CysLT1 receptor is well established, and most of the pathophysiological effects of CysLTs in asthma are mediated by CysLT1 receptor. Several CysLT1 antagonists have been developed to date and are currently in clinical practice. Most common among them are classical CysLT1 receptor antagonists such as montelukast, zafirlukast, pranlukast, pobilukast, iralukast, cinalukast and MK571. The pharmacological role of CysLT2 receptor, however, is less defined and there is no specific antagonist available so far. The recent demonstration that mice lacking both known CysLT receptors exhibit full/augmented response to CysLT points to the existence of additional subtypes of CysLT receptors. LTB4, on the other hand, is another potent inflammatory leukotriene, which acts as a strong chemoattractant for neutrophils, but weaker for eosinophils. LTB4 is known to play an important role in the development of airway hyper-responsiveness in severe asthma. However there is no LTB4 antagonist available in clinic to date. Conclusion: This review gives a recent update on the LTs including their biosynthesis, biological effects and the role of anti-LTs in the treatment of asthma. It also discusses about the possible existence of additional subtypes of CysLT receptors.

Prostaglandin E2 synthase inhibition as a therapeutic target

Background: Most NSAIDs function by inhibiting biosynthesis of PGE2 by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) with a bias towards TXA2 may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Methods: Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E2 synthases. Microsomal prostaglandin E2 synthase-1 (mPGES-1) specifically isomerizes PGH2 to PGE2, under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. Conclusion: mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Hepatocyte growth factor is an attractive target for the treatment of pulmonary fibrosis

Introduction: Pulmonary fibrosis (PF) is a progressive fatal disorder and is characterized by alveolar epithelial injury, myofibroblast proliferation, and extracellular matrix remodeling, resulting in irreversible distortion of lungs architecture. Available therapies are associated with side effects and show restricted efficacy. Therefore, there is an urgent need to find a therapeutic solution to PF. Therapeutic strategies interfering myofibroblast expansion, apoptosis of epithelial and endothelial cells might be beneficial for treatment of PF. Hepatocyte growth factor (HGF), a pleiotropic growth factor, plays an important role in lung development, inflammation, repair, and regeneration. In animal model of PF, administration of recombinant HGF protein or ectopic HGF expression ameliorates fibrosis. Areas covered: The focus of this review is to highlight HGF as a promising therapeutic approach for the treatment of PF. The review discusses the currently available treatment option for PF as well as highlights the possible beneficial effect of HGF as a drug target. Expert opinion: HGF with its anti-fibrotic effect provides a promising new therapeutic approach by protecting lung from fibrotic remodeling and also promoting normal regeneration of lung. The development of HGF mimetics may provide a potential attractive therapy for treatment of this devastating and complex disease.

Chronic obstructive pulmonary disease: role of matrix metalloproteases and future challenges of drug therapy

COPD is a chronic disease of the lung that is characterised by decreased air flow and associated abnormal inflammatory responses of the lungs. A total of 80% of COPD incidences are observed in patients with history of smoking tobacco. The chronic condition of COPD is characterised by airway remodelling, which leads to emphysema and chronic bronchitis. Inflammatory cells of the immune system play a major role in pathophysiology of COPD. High levels of neutrophils, macrophages and CD8+ T cells have been found in bronchoalveolar lavage samples of COPD patients. Matrix metalloproteases (MMPs), which are secreted by these inflammatory cells, have the enzymatic capacity to cause morphological changes in the lungs and contribute significantly to the COPD state. Increased concentrations of MMP-1, -2, -9, -12 and so on have been found in bronchoalveolar lavage samples of COPD patients compared with non-COPD individuals. COPD is rated as among the top five diseases with high mortality rates and it is estimated that in the next 20 years, the healthcare cost alone for COPD will be US

Dual epidermal growth factor receptor (EGFR)/insulin-like growth factor-1 receptor (IGF-1R) inhibitor: a novel approach for overcoming resistance in anticancer treatment.

800 million worldwide. The present drug therapies are neither very efficacious nor cost effective; hence, there is unmet medical need to discover small-molecule drugs for COPD. In this regard, synthetic MMP inhibitors show a great promise for COPD treatment.

Pharmacology of a novel, orally active PDE4 inhibitor.

Small molecule inhibitors of epidermal growth factor receptors (EGFR) have been found to show a good initial response in cancer patients but during the course of treatment, patients develop resistance after a few weeks of time. Development of secondary mutations or over-activation of insulin like growth factor (IGF-1R) pathway are a few of the several mechanisms proposed to explain the resistance. To study the effect of dual inhibition of EGFR and IGF-1R in overcoming the resistance, three strategies were envisaged and are reported in this manuscript: 1) a virtual predictive tumor model, 2) in vitro experimental data using a combination of EGFR and IGF-1R inhibitors and 3) in vitro experimental data using in house dual inhibitors. Findings reported in this manuscript suggest that simultaneous inhibition of IGF-1R and EGFR either by combination of two inhibitors or by dual kinase inhibitors is more efficacious compared to single agents. In vitro cell based experiments conducted using epidermoid cancer cell line, A431 and an EGFR mutant cell line, H1975 along with virtual predictions reported here suggests that dual inhibition of EGFR and IGF-1R is a viable approach to overcome EGFR resistance.