The therapeutic potential of synthetic multivalent carbohydrates

Recent progress has been made in constructing synthetic multivalent carbohydrate ligands targeted at known or probable multivalent carbohydrate ligand receptors. Multivalency can dramatically compensate for the weak affinities of individual carbohydrate ligand moieties. Multivalent branched ligand mimetics have been described bearing multiple mannoside, galactoside, lactoside and Sialyl Lewis X (SLe(x)) moieties. New methods for polymeric backbone construction have provided glyco-polymers of defined and controllable size. Promising examples of multivalent ligands giving significant increases in binding potency are being pursued. These types of agents have extensive therapeutic potential in treating infectious diseases or host abnormalities, and also offer exciting potential as drug-conjugate cell-targeting agents.     

The therapeutic potential of aromatase inhibitors

The third generation aromatase inhibitors are both remarkably potent and specific endocrine agents inhibiting aromatase activity and reducing circulating oestrogen levels in postmenopausal women to levels never previously seen. Their therapeutic potential is consequently much greater than the earlier prototype drugs. Their excellent side-effect profile also allows for potential wider indications in the treatment of oestrogen-related diseases, including breast cancer. It still remains to determine whether their potent endocrine effects translate into increased therapeutic benefit. In advanced breast cancer, aromatase inhibitors have been shown to have improved efficacy and toxicity profiles when compared with progestins, aminoglutethimide and tamoxifen. Aromatase inhibitors have also been used in the neoadjuvant setting, where they have been shown to achieve higher response rates than tamoxifen and to be more successful at downstaging tumours. Early results comparing an aromatase inhibitor with tamoxifen in the adjuvant setting in early breast cancer show anastrozole to be superior to tamoxifen in terms of both disease-free survival and a lower incidence of new contralateral tumours. There was also a more favourable side-effect profile, which has implications for potential future prophylactic treatment. Additionally, since aromatase inhibitors have different mechanisms of action, unlike antioestrogens, they may be particularly useful as chemopreventive agents if oestrogens are themselves genotoxic. Aromatase inhibitors have been used to date almost exclusively in postmenopausal women. The potential of combining them with luteinising hormone-releasing hormone analogues allows the possibility of treating premenopausal women with either oestrogen receptor-positive breast cancer or benign conditions such as cyclical breast pain, fibroadenomata, recurrent cystic disease or endometriosis. There is also the potential for their use in men with conditions such as gynaecomastia or prostate cancer. These new generation aromatase inhibitors may well have an increasing role in the future management of a number of conditions in addition to breast cancer.     

The potential of heparanase as a therapeutic target in cancer

Heparanase has generated substantial interest as therapeutic target for antitumor therapy, because its activity is implicated in malignant behavior of cancer cells and in tumor progression. Increased heparanase expression was found in numerous tumor types and correlates with poor prognosis. Heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, regulates the structure and function of heparan sulfate proteoglycans, leading to disassembly of the extracellular matrix. The action of heparanase is involved in multiple regulatory events related, among other effects, to augmented bioavailability of growth factors and cytokines. Inhibitors of heparanase suppress tumor growth, angiogenesis and metastasis by modulating growth factor-mediated signaling, ECM barrier function and cell interactions in the tumor microenvironment. Therefore, targeting heparanase has potential implications for anti-tumor, anti-angiogenic and anti-inflammatory therapies. Current approaches for heparanase inhibition include development of chemically modified heparins, small molecule inhibitors and neutralizing antibodies. The available evidence supports the emerging utility of heparanase inhibition as a promising antitumor strategy, specifically in rational combination with other agents. The recent studies with compounds designed to block heparanase (e.g., modified heparins) provide a rational basis for their therapeutic application and optimization.     

Carbopeptides: carbohydrates as potential templates for de novo design of protein models

Abstract: De novo design of proteins has evolved into a powerful approach for studying the factors governing protein folding and stability. Among the families of structures frequently studied is the ‘four‐helix bundle’ in which four α‐helical peptide strands, linked by loops, form a hydrophobic core. Assembly of protein models on a template has been suggested as a way to reduce the entropy of folding. Here we describe the potential use of a carbohydrate as such a template. The monosaccharide d ‐galactose was per‐O‐acylated with (N^β‐Fmoc‐βAla)₂O to give a penta‐substituted derivative, which was converted to the corresponding glycosyl bromide and used for the glycosylation of 4‐hydroxymethylbenzoic acid pentafluorophenyl ester (HMBA‐OPfp). The β‐glycosidic carbohydrate template (N^β‐Fmoc‐βAla)₄‐β‐d ‐Galp‐(1‐O)‐MBA‐OPfp thus obtained was coupled to a PAL‐PEG‐PS resin and simultaneously extended at the four arms to yield, after cleavage from the solid support, a carbopeptide with four identical peptide strands. Extension of this concept to, for example, synthesis of novel multiple antigenic peptides (MAPs) and synthesis of carbohydrate clusters can be easily envisioned. The ability to efficiently synthesize such structures sets the stage for further studies to test whether the carbohydrate templates do indeed nucleate folding.     

The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents

Artemisinin derivatives such as artesunate, dihydroartemisinin and artemether are playing an increasing role in the treatment of drug-resistant malaria. They are the most potent antimalarials available, rapidly killing all asexual stages of the parasite Plasmodium falciparum. This review highlights the recent developments in the area of improved second-generation semi-synthetic artemisinin derivatives and fully synthetic antimalarial endoperoxide drugs. In pursuit of synthetic analogues of the artemisinins, one of the major challenges for chemists in this area has been the non-trivial development of techniques for the introduction of the peroxide bridge into candidate drugs. Although chemical research has enabled chemists to incorporate the endoperoxide ‘warhead’ into synthetic analogues of artemisinin, significant drawbacks with many candidates have included comparatively poor antimalarial activity, non-stereoselective syntheses and chemical approaches that are not readily amenable to scale up. However, very recent progress with synthetic 1,2,4-trioxolanes provides a new benchmark for future medicinal chemistry efforts in this area.     

The potential utility of PFKFB3 as a therapeutic target

Introduction: It has been known for over half a century that tumors exhibit an increased demand for nutrients to fuel their rapid proliferation. Interest in targeting cancer metabolism to treat the disease has been renewed in recent years with the discovery that many cancer-related pathways have a profound effect on metabolism. Considering the recent increase in our understanding of cancer metabolism and the enzymes and pathways involved, the question arises as to whether metabolism is cancer’s Achilles heel.

Areas covered: This review summarizes the role of 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in glycolysis, cell proliferation, and tumor growth, discussing PFKFB3 gene and isoenzyme regulation and the changes that occur in cancer and inflammatory diseases. Pharmacological options currently available for selective PFKFB3 inhibition are also reviewed.

Expert opinion: PFKFB3 plays an important role in sustaining the development and progression of cancer and might represent an attractive target for therapeutic strategies. Nevertheless, clinical trials are needed to follow up on the promising results from preclinical studies with PFKFB3 inhibitors. Combination therapies with PFKFB3 inhibitors, chemotherapeutic drugs, or radiotherapy might improve the efficacy of cancer treatments targeting PFKFB3.     

The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents

Artemisinin derivatives such as artesunate, dihydroartemisinin and artemether are playing an increasing role in the treatment of drug-resistant malaria. They are the most potent antimalarials available, rapidly killing all asexual stages of the parasite Plasmodium falciparum. This review highlights the recent developments in the area of improved second-generation semi-synthetic artemisinin derivatives and fully synthetic antimalarial endoperoxide drugs. In pursuit of synthetic analogues of the artemisinins, one of the major challenges for chemists in this area has been the non-trivial development of techniques for the introduction of the peroxide bridge into candidate drugs. Although chemical research has enabled chemists to incorporate the endoperoxide 'warhead' into synthetic analogues of artemisinin, significant drawbacks with many candidates have included comparatively poor antimalarial activity, non-stereoselective syntheses and chemical approaches that are not readily amenable to scale up. However, very recent progress with synthetic 1,2,4-trioxolanes provides a new benchmark for future medicinal chemistry efforts in this area.     

The therapeutic potential of novel cardiotonic agents

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as β-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca²⁺mobilisation (upstream mechanism). These agents are associated with the risk of Ca²⁺ overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca²⁺ overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca²⁺ ions (central and/or downstream mechanisms). Novel Ca²⁺ sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca²⁺ sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.     

The therapeutic potential of NS3 protease inhibitors in HCV infection

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide and afflicts > 170 million people. The HCV-encoded NS3 protease is essential for viral replication and has long been recognised as a prime target for antiviral drugs. However, the peculiar active site structure of this enzyme, a shallow dent on the surface of the protein, has rendered the development of small-molecule inhibitors a highly challenging task. Nevertheless, perseverance and creativity has led to significant progress in this field over the last few years resulting in three compounds that are reported to enter the clinic. The impressive reduction of HCV RNA plasma levels observed with two of these inhibitors (ciluprevir and VX-950) in clinical trials has undoubtedly illustrated the potential of this viral enzyme-targeted drug discovery approach.     

The therapeutic potential of drugs targeting the arginase pathway in asthma

Arginine metabolism by arginases may be of importance in health and disease, either by competing with nitric oxide synthases for the common substrate or by the production of L-ornithine. L-Ornithine serves as a precursor for L-proline and polyamines, which may be involved in tissue remodelling by promoting collagen synthesis and cell proliferation. Arginase activity potentiates airway reactivity by reducing the production of bronchodilatory nitric oxide. Increased arginase activity has been implicated in the development of allergen-induced airway hyper-responsiveness in experimental asthma. In addition, reduced L-arginine availability to inducible nitric oxide synthase by arginase may lead to an increased production of peroxynitrite, contributing to increased airway smooth muscle contractility, airway inflammation and cell damage in this disease. Recent studies demonstrate that the upregulation of arginase by T helper type 2 cytokines in lung tissue as well as in cultured airway fibroblasts indicates a possible role of the enzyme in airway re-modelling. These findings, in conjunction with human studies showing a role for arginase in acute asthma, open a new horizon for the therapeutic potential of drugs targeting the arginase pathway in asthma.     

The potential of PTPN22 as a therapeutic target for rheumatoid arthritis

ABSTRACT

Introduction: PTPN22 encodes a lymphoid-specific tyrosine phosphatase (LYP) that is a master regulator of the immune response. This gene is a major susceptibility factor for a wide range of autoimmune conditions, including rheumatoid arthritis (RA) for which it represents the strongest non-HLA contributor to disease risk. A missense PTPN22 allele (R620W) affecting the protein-protein interaction of LYP with other relevant players was described as the functional variant of the association. This review will focus on the role of PTPN22 in the pathogenic mechanisms underlying RA predisposition and discuss the possibility of developing LYP-based treatment strategies with a potential application in clinical practice.

Areas covered: This review covers the literature showing how PTPN22 is implicated in signalling pathways involved in the autoimmune and autoinflammatory processes underlying RA. Insights obtained from studies aimed at developing novel selective LYP suppressors for treating RA are summarized.

Expert opinion: Targeting key risk factors during the early steps of the disease may represent a good strategy to accomplish complete disease remission. As cumulating evidences suggest that PTPN22 R620W is a gain-of-function variant, a growing interest in developing LYP inhibitors has arisen. The potential efficacy and possible application of such compounds are discussed.     

The therapeutic potential of inhibitors of the trypanothione cycle

There is an urgent need for new drugs in the treatment of human African trypanosomiasis, Chagas’ disease and leishmaniasis. This article provides an overview of current drugs, formulations and their deficiencies. Targets for the design of new drugs and the rational provided for targeting enzymes of the trypanothione cycle are described. Biochemical aspects of the cycle and the currently investigated target trypanothione reductase are discussed as are the several classes of inhibitors and their in vitro potencies. Evidence is provided for considering the tryparedoxins as a new target for antiprotozoal chemotherapy and a summary of glutathione-based inhibitors with significant in vitro activity is reported.     

The therapeutic potential of angiotensin II receptor blockers in the treatment of heart failure

Background: Epidemiological data link erectile dysfunction (ED) and lower urinary tract symptoms (LUTS), two highly prevalent conditions in men, assuming a common pathophysiology. Preliminary data showed that phosphodiesterase type 5 inhibitors (PDE5i) might be a promising class of drugs also for LUTS. Objective: The aim of this review is to provide an overview of current knowledge on the association between ED and LUTS with a particular focus on PDE5i as a viable treatment option for LUTS. Methods: A Medline search was completed using the Medical Subject Headings (MESH^® keywords) ‘erectile dysfunction’ and the expression ‘lower urinary tract symptoms’ in all fields of the database. This search revealed 122 relevant references (all Medline database until 31 October 2008). Results/conclusions: LUTS are an independent risk factor for ED. Although the pathophysiological link between these conditions is not clear, several theories have been described with various levels of supporting data. Current data show that PDE5i reduce obstructive and irritative voiding symptoms but have no effect in uroflowmetry parameters of postvoid residual volume. The combination with α-adrenergic antagonists may be another treatment option for LUTS. However, further research is needed to establish efficacy and safety of PDE5i in the treatment of LUTS.     

The potential of cholesteryl ester transfer protein as a therapeutic target

Introduction: Over recent decades, attempts to ascertain the pro-atherogenic nature of plasma cholesteryl ester transfer protein (CETP) and to establish the relevance of its pharmacological blockade as a promising high density lipoproteins-raising and anti-atherogenic therapy have been disappointing.

Areas covered: The current review focuses on CETP as a multifaceted protein, on genetic variations at the CETP gene and on their possible consequences for cardiovascular risk in human populations. Specific attention is given to physiological modulation of endogenous CETP activity by the apoC1 inhibitor. Finally, the rationale behind the need for selection of patients to treat is discussed in the light of recent studies.

Expert opinion: At this stage one can only speculate on the clinical outcome of pharmacological CETP inhibitors in high-risk populations, but recent advances give cause to adjust the expectations from now on. The CETP effect is probably largely influenced by the overall metabolic state, and whether CETP blockade may be relevant or not in promoting cholesterol disposal is still questioned. The possible need for a careful stratification of patients to treat with CETP inhibitors is outlined. Finally, manipulation of CETP activity should be considered with caution in the context of sepsis and infectious diseases.     

Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

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A New Approach to Explore the Binding Space of Polysaccharide-Based Ligands: Selectin Antagonists

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The therapeutic potential of new investigational hepatitis C virus translation inhibitors

Introduction: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis, hepatocellular carcinoma and liver-related death worldwide. Currently, the anti-HCV armamentarium encompasses several direct-acting antivirals (DAA) that achieve very high response rates and have an excellent tolerability profile. However, they do not represent a final solution for HCV global eradication for at least these two reasons: i) some patients harbour resistant strains to DAAs and cannot benefit from currently available treatments; ii) the cost of these drugs remains very high.

Areas covered: This review summarizes pre-clinical and clinical data regarding HCV translation inhibitors, a new class of drugs currently in the pipeline with novel mechanisms of action.

Expert opinion: The availability of DAAs resolved most issues related to HCV treatment compared with the previous interferon-based therapies. However, there are some patients that cannot achieve a viral clearance with currently available treatments. Therefore, there is still room for new drugs in this setting, providing that they demonstrate an advantage in terms of efficacy, safety, cost or or simplicity of use. Based on preliminary results, at least for some promising molecules (e.g. miravirsen and RG-101), studies on safety and efficacy on this intriguing class of drugs are needed.     

The therapeutic use of dendritic cells transfected with tumour RNA

Recently, it was shown that dendritic cells (DCs) transfected with ribonucleic acid (RNA) coding for a tumour-associated antigen (TAA) or whole tumour RNA are able to induce potent antigen and tumour-specific T cell responses directed against multiple epitopes. The feasibility and efficacy of this approach was tested and analysed in different settings by administration of RNA-transfected DCs in patients with cancer or infectious diseases. In some cases, clinical responses were observed, but the overall effectiveness of this approach has to be demonstrated in further clinical trials.     

The therapeutic potential of leptin

Many studies have reported the difficulty most subjects have in maintaining weight loss. Leptin is a cytokine-like protein made in adipose tissue and is transported into the brain by the blood–brain barrier where it inhibits food intake by altering the expression of hypothalamic neurotransmitters. The discovery of leptin raised the hope that a natural compound had been found that could cause weight loss without adverse effects. However, the majority of obese people have high levels of circulating leptin and it is not surprising that clinical trials published so far have shown that leptin only works effectively to suppress food intake in subjects who are hyperphagic as a result of low leptin levels. Obesity secondary to leptin deficiency is rare, most being associated with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels in the CNS may be required. However, there is evidence that the leptin transport mechanism is saturated at low plasma leptin concentrations, limiting the effectiveness of peripherally-administered hormone. It is concluded that for leptin to have therapeutic potential, it either needs to be modified or the transport system by which leptin enters the brain needs to be upregulated to allow leptin to enter the brain more easily. To achieve effective weight loss, it may also be necessary to overcome central leptin insensitivity by developing agents that act downstream of leptin action.     

The therapeutic potential of flavonoids

Four most widely investigated flavonoids, flavopiridol, catechins, genistein and quercetin are reviewed in this article. Flavopiridol is a novel semisynthetic flavone analogue of rohitukine, a leading anticancer compound from an Indian tree. Flavopiridol inhibits most cyclin-dependent kinases and displays unique anticancer properties. It is the first cyclin-dependent kinase inhibitor to be tested in Phase II clinical trials. Catechin and its gallate are major ingredients in green tea and their anti-oxidant and cancer preventive effects have been widely investigated. A Phase I study of green tea extract GTE-TP91 has been conducted in adult patients with solid tumours. Similarly, genistein is a major ingredient in soybean and has been shown to prevent cancer and have antitumour, anti-oxidant and anti-inflammatory effects. Two antibody-genistein conjugates, B43-genistein and EGF-genistein, are currently in clinical development for the treatment of acute lymphoblastic leukaemia and breast cancer, respectively. Finally, most recent updates of quercetin are briefly described.