Fusion/entry inhibitors as therapies for HIV

A combination of three or more antiretroviral drugs, commonly termed 'highly active antiretroviral therapy' (HAART), has become the standard-of-care treatment for HIV-related disease in the developed world. Since its initiation in the mid 1990s, HAART has led to substantial reductions in both mortality and morbidity. There are, however, significant problems associated with existing therapies including high pill burdens and serious side effects in many patients, as well as the emergence and transmission of drug-resistant HIV variants. There is, therefore, a need for new medicines to treat HIV infections, both from the existing drug classes and, perhaps more importantly, a need for medicines that act against the virus in entirely new ways. In recent years, much has been learned about how HIV enters its target cells and this work has led to the identification of compounds that potently inhibit the individual steps of viral entry. The status of current research focussed on preventing HIV entry is described below.     

Modulation of the Critical Flicker Fusion effects of serotonin reuptake inhibitors by concomitant pupillary changes

RATIONALE: Serotonin reuptake inhibitors (SSRIs) have been attributed CNS-activating properties based on their ability to elevate the Critical Flicker Fusion (CFF) threshold. However, such an interpretation may be questioned since CFF elevations may also be due to SSRI-induced increases in pupil diameter. OBJECTIVES: The effect of pupillary changes on CFF assessment following SSRI administration was investigated in a double blind, crossover study. METHODS: During three periods of 15 days, 21 healthy men and women (30-50 years) received sertraline (50 mg on days 1-8, 100 mg on days 9-15), citalopram (20 mg on days 1-8, 40 mg on days 9-15) and placebo. Assessments were done on days 1, 8 and 15 and consisted of pupillary measurements and CFF assessments with and without pupillary control (a 2-mm artificial pupil) using the Leeds Psychomotor Tester. RESULTS: Both SSRIs induced an acute and steady increase in pupil diameters. CFF thresholds were depressed following acute administration of sertraline and citalopram, but this was only apparent when a control was made for the pupillary changes. No CFF effects were seen at day 8, but CFF was again reduced at day 15, with and without control for pupil size. CONCLUSIONS: Mydriasis masked the detrimental effects of both SSRIs on CFF during the acute assessments. Our results raise questions regarding the validity of the assessment of the behavioural toxicity of SSRIs based on CFF measurements without ample control for pupil size, especially when these concern acute measurements.     

融合蛋白——一种新的生物工程技术

标记亲和多肽片段以其优越性在基因工程中占有重要的地位,介绍了构建融合蛋白的策略,优点及其存在的不足。     

重组融合蛋白Atacicept

Atacicept（TACI—Ig,TACE—Fc5,sTACI）是由默克雪兰诺（Merck Serono）公司开发的一种含有TACI受体胞外BAFF／APRIL结合区域以及人IgG的Fc区域的可溶性重组融合蛋白。在B细胞恶性肿瘤及自身免疫性疾病中,在B细胞激活中起重要作用的肿瘤坏死因子（TNF）超家族成员——     

ACE inhibitors

Edited by P. D'Orlèans-Juste & G. E. Plante Published by Birkhauser [Milestones in drug therapy series] 187 pages, price @116, ISBN 3-7643-5982-X     

PNP inhibitors

Summary Purine nucleoside phosphorylase catalyzes the reversible phosphorolysis of purine ribonucleosides and 2-deoxyribonucleosides to the free base and ribose-1-phosphate or 2-deoxyribose-1-phosphate. PNP isolated from humans is specific for guanosine, inosine and certain analogs, although PNPs from other organisms show varying levels of specificity. Interest in PNP arises from its critical role in purine nucleoside metabolism and in T-cell function, which indicates that inhibitors of this enzyme might be useful in the treatment of T-cell proliferative diseases such as T-cell leukemias and lymphomas, in the suppression of host versus graft response in organ transplant patients, and in the treatment of T-cell-mediated autoimmune diseases. Most potent inhibitors of this enzyme are derivatives of guanine or 8-aminoguanine, including 9-arylmethyl derivatives. Of these, 9-benzylguanines substituted at position 2 or 3 of the phenyl ring by a side chain terminating in a phosphonate moiety are the most potent, with K_i in the nanomolar range. However, these compounds have limited potential as drugs because of their very low cell permeability. As a result, inhibitors of this type that have been tested are effective in whole cells only at concentrations of 100 µM or higher. On the other hand, the three-dimensional structure of human PNP, determined by X-ray crystallography, has been used in designing novel inhibitors of this key enzyme, resulting in several families of membrane-permeable inhibitors with IC₅₀ values in the 6—30 nM range. The inhibition is competitive with respect to both inosine and phosphate. 9-(3-Pyridylmethyl)-9-deazaguanine (BCX-34) was chosen from these inhibitors for further study. Its K_i for the inhibition of human erythrocytic PNP is 31 nM, and its IC₅₀ for inhibition of the proliferation of T cells (CCRF-CEM) is 1.4 µM in the presence of 5.6 µM of 2-deoxyguanosine, which alone has no effect on cells. It did not inhibit the proliferation of B cells (MGL-8) up to 30 µM. Phase I/II clinical studies of a dermal formulation of BCX-34 have shown this drug to be efficacious and safe in the treatment of cutaneous T-cell lymphoma and psoriasis.     

PARP inhibitors

Poly(ADP-ribose) polymerase (PARP) catalyzes the biochemical conversion of nicotinamide adenine dinucleotide (NAD+) to poly(ADP-ribose) and nicotinamide, which is a weak feedback inhibitor of the enzyme. Early designs of PARP inhibitors were primarily based on mimicking the structure of nicotinamide and resulted in the identification and widespread use of benzamide analogs as PARP inhibitors. Recent searches for more potent and specific PARP inhibitors, facilitated by the crystal structure of the catalytic domain of PARP, led to several families of amide and lactam derivatives with multiple ring systems. New PARP inhibitors have shown efficacies in several animal disease models of cancer, ischemia and inflammation.     

Aromatase inhibitors

Oestrogens play an active role in the development of numerous hormone-related disorders, most notably hormone-dependent carcinomas, such as those associated with breast and endometrial tissues. A decrease in oestrogen levels can be achieved by inhibition of aromatase, a key enzyme responsible for oestrogen biosynthesis. A third generation of effective and selective aromatase inhibitors (AIs) has recently been developed for clinical use in postmenopausal breast cancer. The patents discussed in this review describe the synthesis and activities of some novel AIs and the use of AIs for the treatment of hormone-dependent disorders.     

b-Lactamase inhibitors

The use of β-lactamase inhibitors in combination with a β-lactamase-susceptible antibiotic is a useful strategy to rescue otherwise good antibiotics from failure. However, recent years have seen a rise in the numbers of β-lactamases that are insensitive to the available β-lactamase inhibitors. This review summarizes of the mechanisms of action of the principal types of inhibitors and the ways in which β-lactamase are thought to develop resistance towards them. Ten general classes of inhibitors are reviewed, especially those of therapeutic importance (clavulanic acid, penam sulfones and carbapenems).     

Elastase inhibitors

Two applications claim novel 1,4-bisphenyl-1,4-dihydropyridine derivatives; 2-hydroxy and 2-aminodihydropyridines, respectively. The compounds are claimed to be useful as neutrophil elastase inhibitors and also in the treatment of both chronic obstructive pulmonary disease and myocardial infarction. These compounds represent yet another use of the widely employed 1,4-dihydropyridine privileged structure.     

Pyridinone-thrombin inhibitors

Thrombin plays a pivotal role in thrombosis and haemostasis. Inhibitors of thrombin are expected to provide a new advantageous route for antithrombotic therapy. This patent from Merck discloses a series of low molecular weight, noncovalent thrombin inhibitors and claims them as useful in preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischaemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build-up of fibrin and reocclusion or restenosis of recanalised vessels.     

Carboxylesterase inhibitors

INTRODUCTION: Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. AREAS COVERED: This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. EXPERT OPINION: The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties and potential uses of such agents are discussed here.     

Phosphodiesterase inhibitors

Phosphodiesterases are a diverse family of enzymes that hydrolyse cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cAMP and cGMP, and hence cell function. Theophylline and papaverine have historically been used therapeutically and are known to be weak inhibitors of PDE, but to what extent this contributed toward their clinical efficacy was poorly defined. However, the discovery of 11 isoenzyme families and our increased understanding of their function at the cell and molecular level provides an impetus for the development of isoenzyme selective inhibitors for the treatment of various diseases. This review focuses on the development of PDE3 inhibitors for congestive heart failure, PDE4 inhibitors for inflammatory airways disease and most successfully, PDE5 inhibitors for erectile dysfunction.     

Aromatase inhibitors

The new non-steroidal and steroidal aromatase inhibitors are at least as effective as megestrol acetate (MA) as second-line hormonal agents in postmenopausal women with breast cancer. However, they are superior to MA in terms of tolerability and adverse effects. Letrozole and exemestane have been shown to be superior to MA in terms of efficacy. Furthermore, exemestane and anastrozole demonstrated a survival advantage over MA. These drugs are therefore considered established second-line hormonal agents. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors as first-line therapy for ER-and/or PgR-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor positive tumours unsuitable for breast conserving surgery. Studies comparing these drugs head-to-head and with adjuvant tamoxifen are currently in progress. The potential role of these drugs in breast cancer prevention is worth investigating.     

Fusion of disubstituted benzenes.

The entropy of fusion of 84 disubstituted benzenes was essentially constant and independent of the participation of the compounds in intramolecular or intermolecular hydrogen bonding. It was also independent of the shapes, sizes, and dipole moments of the rigid molecules studied. While the entropy of fusion was independent of these parameters, the melting point and the heat of fusion showed a direct dependence on molecular properties.