多靶点配体与药物设计

综述有关多靶点配体药物设计的基本原理和方法,包括整合共有药效团法、轭合药效团法、可分解轭合药效团法及筛选法;并讨论多靶点配体与合理药物设计的关系以及设计中应注意的问题,为新药的研究与开发提供参考。     

Designing oral vaccines targeting intestinal dendritic cells

Introduction: Most pathogens colonize and invade the host at mucosal surfaces, such as the lung and the intestine. To combat intestinal pathogens the induction of local adaptive immune responses is required, which is mainly achieved through oral vaccination. However, most vaccines are ineffective when given orally owing to the hostile environment in the gastrointestinal tract. The encapsulation of antigens in biodegradable microparticulate delivery systems enhances their immunogenicity; however, the uptake of these delivery systems by intestinal immune cells is rather poor. Surface decoration of the particulates with targeting ligands could increase the uptake and mediate the selective targeting of the vaccine to intestinal antigen-presenting cells, including dendritic cells.

Areas covered: In this review, current knowledge on dendritic cell subsets is discussed, along with progress in the development of selective antigen targeting to these cells, in addition to focusing on data obtained in mice and, where possible, the pig, as a non-rodent animal model for humans. Moreover, the potential use and benefits of Fcγ receptor-mediated targeting of antigen delivery systems are highlighted.

Expert opinion: In conclusion, dendritic cell targeting ligands grafted on antigen carrier systems should preferably bind to a conserved endocytotic receptor, facilitating the design of a multispecies vaccine platform, which could elicit robust protective immune responses against enteric pathogens.     

NMDA receptor activation antagonizes the NMDA antagonist-induced antianxiety effect in the elevated plus-maze test in mice

BackgroundThe purpose of this study was to determine how the activation of different regulatory domains of the NMDAcomplex affects the antianxiety effect of antagonists acting at its distinct binding sites.MethodsThe anxiolytic-like activity was assessed by the elevated plus-maze test in mice.ResultsThe anxiolytic activity of CGP 37849 (a competitive NMDAreceptor antagonist) and L-701,324 (an antagonist at glycine site) was confirmed, but effects of both were significantly reduced by N-methyl-D-aspartic acid (NMDA) or by D-serine agonists at glutamate and glycine site of the NMDA receptor complex, respectively.ConclusionThe obtained data suggest that stimulation of the glutamate or glycine recognition site of the NMDAreceptor complex significantly decreases the antianxiety properties of antagonists of either site.     

Cannabinoid receptor antagonists: pharmacological opportunities,clinical experience,and translational prognosis

The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimon-abant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant's market withdrawal in the European Union and suspension of rimonabant's, taranabant's, and otenabant's ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.     

Telomerase inhibition as an adjuvant anticancer therapy: it is more than just a waiting game

Background: There is increasing evidence that Toll-like receptors (TLRs) sense host tissue damage by engaging with endogenous ligands. TLRs are considered to be involved in many primarily non-immune-related diseases. Hepatic ischemia reperfusion injury (IRI) represents one of these disorders. Objective: To present the latest findings supporting the involvement of TLRs in liver IRI and to explore their role as potential targets for therapeutic intervention. Methods: A review of the literature summarizing the latest advances in TLR signaling, the role of TLRs in each hepatic cell population and the involvement of TLRs in the pathophysiology of hepatic IRI. The potential role of TLR-targeting treatment strategies in liver IRI is discussed. Conclusions: Recent experimental evidence suggests that TLR activation on Kupffer cells provides the triggering signal for pro-inflammatory responses that lead to liver IRI. Modulating TLR signaling could have a beneficial effect in patients with liver IRI.     

Latest advances in cannabinoid receptor agonists

Background: Since the discovery of cannabinoid receptors and their endogenous ligands in early 1990s, the endocannabinoid system has been shown to play a vital role in several pathophysiological processes. It has been targeted for the treatment of several diseases including neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's disease and MS), cancer, obesity, inflammatory bowel disease, neuropathic and inflammatory pain. The last decade has witnessed remarkable advances in the development of cannabinergic ligands displaying high selectivity and potency towards two subtypes of cannabinoid receptors, namely CB1 and CB2. Objective: In this review, we highlight the latest advances made in the development of cannabinoid agonists and summarize recently disclosed, novel chemical scaffolds as CB-selective agonists in patents that appeared during January 2008 – June 2009. Methods: Data presented here are obtained through the search of PubMed for research articles and reviews, and the website of European patents (http://ep.espacenet.com), SciFinder Scholar? and US patents (www.uspto.gov). Conclusions: Our analysis reveals prolific patenting activity mainly in the CB2 selective agonist area. Limiting the BBB penetrability, thereby, leading to peripherally restricted CB1/CB2 agonists and enhancing CB2-selectivity emerge as likely prerequisites for avoidance of adverse central CB1 mediated side effects.     

5HT6 receptor antagonists: a patent update. Part 1. Sulfonyl derivatives

Introduction: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5HT receptors (5HT₆Rs) are highly attractive as important biological targets with enormous clinical importance. Among this subclass, 5HT₆R is the most recently discovered group. Available biological data clearly indicate that 5HT₆R antagonists can be used as effective regulators in a variety of contexts, including memory formation, age-related cognitive impairments and memory deficits associated with conditions such as schizophrenia, Parkinson's disease and Alzheimer's disease. Therefore, this receptor has already attracted a considerable attention within the scientific community, due to its versatile therapeutic potential.

Areas covered: The current paper is an update to the comprehensive review article published previously in Expert Opinion on Therapeutic Patents (see issue 20(7), 2010). Here, the main focus is on small-molecule compounds – 5HT₆ antagonists – which have been described in recent patent literature, since the end of 2009. To obtain a clear understanding of the situation and dynamic within the field of 5HT₆ ligands, having an obvious pharmaceutical potential in terms of related patents, a comprehensive search through several key patent collections have been provided. The authors describe the reported chemical classes and scaffolds in sufficient detail to provide a valuable insight in the 5HT₆R chemistry and pharmacology. The review consists of two core parts with separate sections arranged in accordance with the main structural features of 5HT₆R ligands.

Expert opinion: Recent progress in the understanding of the 5HT₆ receptor function and structure includes a suggested constitutive activity for the receptor, development of a number of multimodal small molecule ligands and re-classification of many selective antagonists as pseudo-selective agents. Heterocycles with sulfonyl group and without any basic center provide sufficient supramolecular interactions and show high antagonistic activity against 5HT₆R.     

病毒性心肌炎患者外周血肿瘤坏死因子配体相关分子1A表达水平及临床意义

目的 探讨肿瘤坏死因子配体相关分子1A(TL1A)在病毒性心肌炎患者外周血中的表达水平及临床意义.方法 分别采用酶联免疫吸附试验法和实时定量PCR法检测70例病毒性心肌炎患者(病毒性心肌炎组)及70例健康体检者(对照组)血浆TL1A水平和外周血TL1A mRNA的表达水平.结果 病毒性心肌炎组血浆TL1A水平[(1.37±0.41) μg/L]明显高于对照组[(0.85±0.22)μg/L],差异有统计学意义(P=0.000);病毒性心肌炎组外周血TL1A mRNA水平(0.39±0.17)明显高于对照组(0.31±0.11),差异有统计学意义(P=0.001).结论 病毒性心肌炎患者外周血TL1A表达水平升高,TL1A可能参与了病毒性心肌炎的发病过程.     

Structure-based biological investigations on ruthenium complexes containing 2,2′-bipyridine ligands and their applications in photodynamic therapy as a potential photosensitizer

Ruthenium complexes have been investigated for various biological applications by virtue of their radical scavenging, DNA binding, receptor binding, and cytotoxic abilities; especially the possible potential application of these complexes in photodynamic therapy (PDT). This study focuses on the synthesis, structural characterization and biological application (pertaining to its cytotoxicity and radical generation) of ruthenium complexed with salicylaldehyde fumaryl-dihydrazone (slfhH₄), salicylaldehyde glutaryl-di-hydrazone (slfgH₄) and 2,2′-bipyridine (bpy). During the synthesis, the anticipated complex was precipitated out but as serendipity, Ruthenium(II) tris (2,2′-bipyridyl) monochloride nonahydrate {[Ru(bpy)₃]²⁺.Cl.9H₂O} (RBMN) and Ruthenium(II) tris (2,2′-bipyridyl) monochloride septahydrate {[Ru(bpy)₃]²⁺.Cl.7H₂O}(RBMS) were crystallized from the filtrate. The crystal structure of complexes RBMN and RBMS were determined by a single-crystal X-ray diffraction methods and it showed that chlorine anion lies at the crystallographic axis and forms a halogen hydrogen-bonded organic framework (XHOF) to provide the stability. In comparison with similar structures in Cambridge Crystallographic Data Center (CCDC) revealed that the nature of the XHOF framework and the layered packing are conserved. The compounds showed excellent cytotoxic ability (against L6 cells) and the nitro blue tetrazolium (NBT) assay upon irradiation to light revealed its ability to produce reactive oxygen species (ROS). The presence of partially occupied water molecules in the layered organization within the crystal packing mimics the release of ROS resulting in cytotoxicity. The structural results together with the biological data make these complexes interesting candidates for potential photosensitizers for PDT applications.