Current Medicinal Chemistry (v.20, #20)
Sulfated Glycosaminoglycans As Promising Artificial Extracellular Matrix Components to Improve the Regeneration of Tissues by M. Schnabelrauch, D. Scharnweber, J. Schiller (2501-2523).
Glycosaminoglycans (GAG) such as hyaluronan (HA) or chondroitin/dermatan sulfate (CS/DS) occur in manyconnective tissues, for instance, in bone, cartilage and skin. Due to their significant water-binding capacity, GAG are essentialfor the biomechanical properties of these tissues. However, there is also increasing evidence that the sulfation ofGAG does not occur at random, but a "sulfation code" exists that mediates the physiological functions of GAG. Thus, thebiological properties of these biomacromolecules are strongly influenced by the degree of sulfation (ds) and the sulfategroup distribution along the polymer. Therefore, certain GAG might also have interesting pharmacological properties. Itis, thus, commonly accepted that GAG represent promising biomaterials in the field of tissue engineering as well as to designnew bioactive materials for tissue repair and reconstruction. In this review we will focus on chemically sulfated GAGand provide a survey of these compounds on four different levels. First, we will provide an overview on chemical functionalizationstrategies of naturally occurring HA and CS/DS with special emphasis on regioselective methods to introducea defined number of sulfate residues into the carbohydrate backbone. Second, chemical and biochemical methods tocharacterize the synthesized compounds will be introduced with the focus on methods based on nuclear magnetic resonance(NMR) and mass spectrometry (MS). In the third part, we will discuss the interaction of natural and chemically sulfatedGAG with proteins and other biomolecules with regulatory functions. Additionally, biological consequences of theseinteractions regarding healing processes of skin and bone will be presented by discussing selected cell culture experiments.Finally, in vivo effects of GAG as components of artificial extracellular matrices will be discussed.
Hetero-Oligomerization of Chemokine Receptors: Diversity and Relevance for Function by S. Kraemer, S. Alampour- Rajabi, O. El Bounkari, J. Bernhagen (2524-2536).
The G protein-coupled receptor (GPCR) family of membrane receptors encompasses over 1000 members, representingthe largest known receptor family, with a variety of structurally different ligands. GPCRs are favorite targets fordrug development in numerous diseases. Chemokine receptors are an important GPCR sub-class and are known to play acrucial role in the regulation of multiple physiological and various pathophysiological processes, including inflammation,atherosclerosis, cancer, and viral infections. Chemokine receptor activation is controlled by some 50 chemokine ligandswhich often act in a redundant and overlapping manner, enabling for a complex regulatory system together controlling andfine-tuning the specificity and spatio-temporal properties of the response. Recent findings have indicated that additionallythe organization of chemokine receptors on the cell surface could be critical for driving their biological effects. In fact,chemokine receptors have increasingly been found to organize into homo- or hetero-oligomeric complexes, in part in aligand-inducible manner, resulting in complex networks and crosstalk with other orthogonal signaling complexes. Therehas even been evidence for heterologous complex formation between chemokine receptors and non-chemokine receptor Gprotein-coupled receptors (GPCRs), and even non-GPCRs. However, the functional consequences of this kind of oligomerizationhave remained poorly understood, even for the chemokine receptor homo-oligomers. Yet, there is growingevidence that targeting homo- and/or hetero-oligomerization of chemokine receptors might be beneficial for the developmentof novel and specific therapeutics. In the present article, we highlight the multi-faceted complexity of chemokine receptorstructures with a focus on their hetero-oligomerization properties.
Clinical and Marketed Proteasome Inhibitors for Cancer Treatment by Jiankang Zhang, Peng Wu, Yongzhou Hu (2537-2551).
The ubiquitin-proteasome pathway (UPP), which influences essential cellular functions including cell growth,differentiation, apoptosis, signal transduction, antigen processing and inflammatory responses, has been considered as oneof the most important cellular protein degradation approaches. Proteasome functions as a gatekeeper, which controls theexecution of protein degradation and plays a critical role in the ubiquitin-proteasome pathway. The unfolding of the closeconnection between proteasome and cancer provides a potential strategy for cancer treatment by using proteasome inhibitors.Small molecular inhibitors of varied structures and potency against proteasome have been discovered in recent years,with bortezomib and carfilzomib having been successfully approved for clinical application while some other promisingcandidates are currently under clinical trials. Herein, we review the development history of drugs and candidates that targetthe 20S proteasome, structure-activity relationships (SARs) of various proteasome inhibitors, and related completed orongoing clinical trials.
Selectivity Problems with Drugs Acting on Cardiac Na+ and Ca2+ Channels by Bence Hegyi, Istvan Komaromi, Peter P. Nanasi, Norbert Szentandrassy (2552-2571).
With the increase of our knowledge on cardioactive agents it comes more and more clear that practically noneof the currently used compounds shows absolute selectivity to one or another ion channel type. This is particularly true forNa<sup>+</sup> and Ca<sup>2+</sup> channel modulators, which are widely applied in the clinical practice and biomedical research. The best examplemight be probably the marine guanidine poison tetrodotoxin, which has long been considered as a selective Na<sup>+</sup>channel blocker, while recently it turned out to effectively inhibit cardiac Ca<sup>2+</sup> currents as well. In the present study thecross actions observed between the effects of various blockers of Na<sup>+</sup> channels (such as toxin inhibitors, class I antiarrhythmicsand local anesthetics) and Ca<sup>2+</sup> channels (like phenylalkylamines, dihydropyridine compounds, diltiazem andmibefradil) are overviewed in light of the known details of the respective channel structures. Similarly, activators of Na<sup>+</sup>channels, including veratridine and batrachotoxin, are also compared. The binding of tetrodotoxin and saxitoxin to Cav1.2and Nav1.5 channel proteins is presented by construction of theoretical models to reveal common structures in their poreforming regions to explain cross reactions. Since these four domain channels can be traced back to a common ancestor, aclose similarity in their structure can well be demonstrated. Thus, the poor selectivity of agents acting on cardiac Na<sup>+</sup> andCa<sup>2+</sup> channels is a consequence of evolution. As a conclusion, since the limited selectivity is an intrinsic property of drugreceptors, it has to be taken into account when designing new cardioactive compounds for either medical therapy or experimentalresearch in the future.
Bioavailability of Quercetin: Problems and Promises by X. Cai, Z. Fang, J. Dou, A. Yu, G. Zhai (2572-2582).
Quercetin (QC) is a typical plant flavonoid, possesses diverse pharmacologic effects including antiinflammatory,antioxidant, anti-cancer, anti-anaphylaxis effects and against aging. However, the application of QC inpharmaceutical field is limited due to its poor solubility, low bioavailability, poor permeability and instability. To improvethe bioavailability of QC, numerous approaches have been undertaken, involving the use of promising drug delivery systemssuch as inclusion complexes, liposomes, nanoparticles or micelles, which appear to provide higher solubility andbioavailability. Enhanced bioavailability of QC in the near future is likely to bring this product to the forefront of therapeuticagents for treatment of human disease.
The Multifunctional Anti-inflammatory Drugs Used in the Therapy of Alzheimerµs Disease by S. Shi, Z. Wang, Z. Qiao (2583-2588).
Inflammation has recently been implicated as a critical mechanism in Alzheimer's disease (AD). Microglia arethe resident immune cells in the central nervous system (CNS), and they mediate the inflammatory response in the ADbrain. Thus, suppression of microglial activation and subsequent neuroinflammation may be a potential therapeutic approachagainst AD. In the following review, we briefly discuss the limitations and advantages of current drug targets forAD and then summarize several anti-inflammatory drugs in trial, including natural nonsteroidal anti-inflammatory drugs(NSAIDs), polyphenols and new drugs synthesized based on multi-target directed ligand (MTDL) design. In addition totheir anti-inflammatory effects, these drugs can act as anti-oxidants and reduce microglial activation or amyloid-β (Aβ)plaques. Thus, the studies focused on multiple factors in AD processes might reveal the best potential treatment strategyfor the future.
Functionalized Mesoporous Silica Nanoparticles: A Possible Strategy to Target Cancer Cells Reducing Peripheral Nervous System Uptake by C. Ceresa, G. Nicolini, R. Rigolio, M. Bossi, L. Pasqua, G. Cavaletti (2589-2600).
Mesoporous silica materials (MSM) have been proposed as promising tools for cell specific drug delivery orfluorescent cell tracking. In cancer therapy there is an urgent need to develop a cancer cell specific drug carrier able tolimit the non-specific uptake of the drug by normal cells thereby reducing serious side effects. Chemotherapy induced peripheralneurotoxicity (CIPN) is one of the most clinically relevant side effects linked to the use of several antineoplasticdrugs. In this study we showed that the uptake of MSM (synthesized using a PEG surfactant-based interfacial synthesisprocedure), functionalised with folic acid (MSM-FOL) after 1, 6 and 24 hours is very limited in neuronal-like cellular systemssuch as differentiated SH-SY5Y human neuroblastoma cells and rat embryonic dorsal root ganglia sensory neurons.By contrast, the nanoparticles are highly internalized in A549 and IGROV-1 cancer cells. The 6 hour-treatment of A549and IGROV-1 cells with nanoparticles loaded with the antineoplastic drug cisplatin (CP) induced significant cytotoxicitywith respect to CP alone. These results were observed treating IGROV-1 cells with 25 and 50 μg/ml nanoparticles doses(corresponding respectively to CP 6.25 and 12.5 μM) and treating A549 with 50 μg/ml.Our results demonstrated a selectiveuptake of functionalized MSM suggesting them as promising tools for targeted antineoplastic therapy. Further studieswill be necessary in order to confirm if this approach may be useful in reducing neurotocity of anticancer drugs.
Functional Characterization of a PEI-CyD-FA-Coated Adenovirus as Delivery Vector for Gene Therapy by Hong Yao, Shih-Chi Chen, Zan Shen, Yun-Chao Huang, Xiao Zhu, Xiao-mei Wang, Wenqi Jiang, Zi-Feng Wang, Xiu-Wu Bian, Eng-Ang Ling, Hsiang-fu Kung, Marie C. Lin (2601-2608).
The recombinant adenovirus is evolving as a promising gene delivery vector for gene therapy due to its efficiencyin transducing different genes into most types of cells. However, the host-immune response elicited by primary inoculationof an adenovirus can cause rapid clearance of the vector, impairing the efficacy of the adenovirus and hence obstructingits clinical application. We have previously synthesized a biodegradable co-polymer consisting of a low molecularweight PEI (MW 600 Da), cross-linked with β-cyclodextrin, and conjugated with folic acid (PEI-CyD-FA, namedH1). Here we report that coating the adenovirus vector (Adv) with H1 (H1/rAdv) could significantly improve both the efficacyand biosafety of Adv. Enhanced transfection efficiency as well as prolonged duration of gene expression wereclearly demonstrated either by intratumoral or systemic injection of a single dose of H1/rAdv in immunocompetent mice.Importantly, repeated injections of H1/rAdv did not reduce the transfection efficiency in immunocompetent mice. Furthermore,H1 transformed the surface charge of the adenovirus capsomers from negative to positive in physiological solution,suggesting that H1 coated the capsid protein of the adenovirus. This could shelter the epitopes of capsid proteins ofthe adenovirus, resulting in a reduced host-immune response and enhanced transfection efficiency. Taken together, thesefindings suggest that H1/rAdv is an effective gene delivery system superior to the adenovirus alone and that it could beconsidered as a preferred vehicle for gene therapy.