Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 13, Number 27, 2006

Contents


Surfactant Protein A – From Genes to Human Lung Diseases Pp. 3239-3252
S. Heinrich, D. Hartl and M. Griese
[Abstract]


Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and COPD Pp. 3253-3262
Zheng Huang and Joseph A. Mancini
[Abstract]


Progress in Computational Approach to Drug Development Against SARS Pp. 3263-3270
Kuo-Chen Chou, Dong-Qing Wei, Qi-Shi Du, Suzanne Sirois and Wei-Zhu Zhong
[Abstract]


Reactions of Myeloperoxidase-Derived Oxidants with Biological Substrates: Gaining Chemical Insight into Human Inflammatory Diseases Pp. 3271-3290
D.I. Pattison and M.J. Davies
[Abstract]


Mechanisms of Cellular Resistance to Camptothecins Pp. 3291-3305
G.L. Beretta, P. Perego and F. Zunino
[Abstract]


The Role of Growth Hormone, Insulin-Like Growth Factor and Somatostatin in Diabetic Retinopathy Pp. 3307-3317
Jennifer L. Wilkinson-Berka, Christopher Wraight and George Werther
[Abstract]


Recent Developments in Search of Antifilarial Agents Pp. 3319-3334
Rama Pati Tripathi, Diksha Katiyar, Namrata Dwivedi, Biswajit K. Singh and Jyoti Pandey
[Abstract]


Bacteriocins as Oral and Gastrointestinal Antibiotics: Theoretical Considerations, Applied Research, and Practical Applications Pp. 3335-3350
B.C. Kirkup, Jr.
[Abstract]


Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research Pp. 3351-3357
Stefan Russmann, Ignazio Grattagliano, Piero Portincasa, Vincenzo O. Palmieri, and Giuseppe Palasciano
[Abstract]




Abstracts


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Surfactant Protein A – From Genes to Human Lung Diseases
S. Heinrich, D. Hartl and M. Griese

Surfactant associated protein-A (SP-A) is the most abundant pulmonary surfactant protein and belongs to the family of innate host defense proteins termed collectins. Besides pulmonary host defense, SP-A is also involved in the formation of pulmonary surfactant, as it is essential for the structure of tubular myelin. The human SP-A gene locus includes two functional genes, SFTPA1 and SFTPA2 which are expressed independently, and a pseudo gene. The largest amount of SP-A1 proteins assemble to larger molecular complexes, whereas SP-A2 forms mainly dimers and trimers. SP-A polymorphisms play a role in respiratory distress syndrome, allergic bronchopulmonary aspergillosis and idiopathic pulmonary fibrosis. The levels of SP-A are decreased in the lungs of patients with cystic fibrosis, respiratory distress syndrome and further chronic lung diseases. Future areas for clinical research include disease specific SP-A expression pattern and their functional consequences, the differential roles of SP-A1 and SP-A2 in human lung diseases, and therapeutical approaches to correct altered SP-A levels.


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Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and COPD
Zheng Huang and Joseph A. Mancini

Type 4 cyclic nucleotide phosphodiesterases (PDE4s) are metallo-hydrolases which specifically hydrolyze cAMP to AMP in various cells types. The catalytic core is a bimetallic ion center composed of a tightly bound Zn²⁺ and a loosely bound Mg²⁺, which plays a dictating role in eliciting cAMP binding and catalysis activation. An invariant glutamine positioned opposite to the ion center serves as the substrate recognition determinant and synergizes the transient Mg-oxo-phosphate interaction in the substrate complex. The Mg²⁺ binding is activated by a PKA-mediated serine phosphorylation and modulated through protein-protein interactions, thus, providing efficient mechanisms in the temporal regulation of cAMP signaling. Several PDE4 inhibitors including roflumilast, cilomilast and rolipram also rely on the interaction with the glutamine and metallic ion center for binding, with their affinity enhanced dramatically by the presence of the Mg²⁺ ion. Recent studies have provided new insights into the role of this enzyme in inflammatory settings, CFTR regulation, long term potentiation, and its importance in immune surveillance. The major inflammatory cytokines which are modulated with PDE4 inhibitors include TNFα, IL-2, IFNγ, IL-12, GM-CSF and LTB₄. The role of PDE4 inhibitors in modulating cytokines, lipid mediators and in mucociliary clearance, along with clinical efficacy in asthma and/or COPD demonstrated with roflumilast and cilomilast, suggest a broad anti-inflammatory spectrum for these compounds. Presently, the major impediment to approval of these novel therapies has been the mechanism based gastrointestinal adverse events which has limited the dosing and the ultimate efficacy with these novel therapeutic agents.


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Progress in Computational Approach to Drug Development Against SARS
Kuo-Chen Chou, Dong-Qing Wei, Qi-Shi Du, Suzanne Sirois and Wei-Zhu Zhong

Since the outbreak of SARS (severe acute respiratory syndrome) in November 2002 in Southern China’s Guangdong Province, considerable progress has been made in the development of drugs for SARS therapy. The present mini review is focused on the area of computer-aided drug discovery, i.e., the advances achieved mainly from the approaches of structural bioinformatics, pharmacophore modeling, molecular docking, peptide-cleavage site prediction, and other computational means. It is highlighted that the compounds C₂₈H₃₄O₄N₇Cl, C₂₁H₃₆O₅N₆ and C₂₁H₃₆O₅N₆ (Wei et al., Amino Acids, 2006, 31: 73-80), as well as KZ7088 (Chou et al. Biochem. Biophys. Res. Commun., 2003, 308: 148-151), a derivative of AG7088, might be the promising candidates for further investigation, and that the octapeptides ATLQAIAS and ATLQAENV, as well as AVLQSGFR, might be converted to effective inhibitors against the SARS enzyme. Meanwhile, how to modify these octapeptides based on the “distorted key” theory to make them become potent inhibitors is explicitly elucidated. Finally, a brief introduction is given for how to use computer-generated graphs to rapidly diagnose SARS coronavirus.


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Reactions of Myeloperoxidase-Derived Oxidants with Biological Substrates: Gaining Chemical Insight into Human Inflammatory Diseases
D.I. Pattison and M.J. Davies

The heme enzyme myeloperoxidase (MPO) is released at sites of inflammation by activated leukocytes. A key function of MPO is the production of hypohalous acids (HOX, X = Cl, Br) which are strong oxidants with potent antibacterial properties. However, HOX can also damage host tissue when produced at the wrong place, time or concentration; this has been implicated in several human diseases. Thus, elevated blood and leukocyte levels of MPO are significant independent risk factors for atherosclerosis, and specific markers of HOX-mediated protein oxidation are often present at elevated levels in patients with inflammatory diseases (e.g. asthma).

HOX react readily with amino acids, proteins, carbohydrates, lipids, nucleobases and antioxidants. Sulfur-containing amino acids (Cys, Met, cystine) and amines on amino acids, nucleobases, sugars and lipids are the major targets for HOX. Reaction with amines generates chloramines (RNHCl) and bromamines (RNHBr), which are more selective oxidants than HOX and are key intermediates in HOX biochemistry. As these and other products of MPO-derived oxidants are unstable, understanding the role of HOX-induced damage in disease cannot be obtained solely by stable product analysis, and knowledge of the reaction kinetics is essential.

This review collates kinetic and product data for HOX, chloramine and bromamine reactions with biological substrates. It highlights how kinetic data may be used to predict the effect of HOX-mediated oxidation on complex biological targets, such as lipoproteins and extracellular matrix in atherosclerosis, or protein-DNA complexes in cancer, thereby providing a basis for unraveling the mechanisms by which these oxidants generate biological damage.


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Mechanisms of Cellular Resistance to Camptothecins
G.L. Beretta, P. Perego and F. Zunino

The camptothecins are among the most promising antitumor agents endowed with a unique mechanism of action, because they act through inhibition of DNA topoisomerase I, an enzyme involved in regulating critical cellular functions including DNA replication, transcription and recombination. On the basis of the pharmacological interest of camptothecins in cancer chemotherapy, medicinal chemistry has played a crucial role in the development of novel analogs, and recently some compounds have emerged as promising agents for clinical evaluation. A major limitation to the clinical efficacy of camptothecin-containing therapies is represented by drug resistance. As with other cytotoxic drugs, clinical resistance to camptothecins may be a multifactorial phenomenon likely involving pharmacological and tumor-related factors. An additional problem in understanding clinically relevant resistance mechanisms is the observation that preclinical cell/tumor models may be not adequately predictive of clinical resistance. Here, we review the mechanisms of cell sensitivity/resistance to camptothecins and current approaches to overcome specific mechanisms, either by chemical modifications or by combination with modulating agents. In particular, the realization that most camptothecins are substrates for ATP binding cassette transporters has stimulated efforts in molecular design of novel non-cross-resistant analogs. Finally, a better understanding of the mechanism of cell response at a cellular level could help in defining new strategies to over-come resistance as well as chemical features required for efficacy.


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The Role of Growth Hormone, Insulin-Like Growth Factor and Somatostatin in Diabetic Retinopathy
Jennifer L. Wilkinson-Berka, Christopher Wraight and George Werther

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are implicated in the aberrant cell growth and pathological neovascularization that characterises proliferative diabetic retinopathy. While serum levels of IGF-I are reported to be either high or low in diabetic patients, there is evidence that local tissue levels of IGF-I may be more relevant to diabetic retinal pathology. IGF-I and IGF binding proteins (IGFBP) are expressed throughout the retina in vascular, neuronal and glial cells, and are altered in response to hyperglycaemia and hypoxia. Further support for a pathological role for local IGF-I comes from studies showing IGF-I to be increased in the vitreal fluids of patients with proliferative diabetic retinopathy. IGF-I may exert its cell growth promoting properties by stimulating a number of pathways including protein-kinase B (Akt), nuclear factor κB (NF-κB)/AP-1 and hypoxic-inducible factor-1α (HIF-1α). In addition, other growth factors may participate in IGF-I induced cell growth including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and fibroblast growth factor (FGF). The importance of the GH/IGF system in diabetic retinopathy and retinal neovascularization has been highlighted by the use of agents that inhibit the system. GH receptor antagonists, GH receptor antisense oligonucleotides, somatostatin analogues and receptor neutralising antibodies to IGF-I reduce hypoxic-induced retinal neovascularization. These approaches may also prove to have benefits for improving vascular patency and vision in patients with diabetic retinopathy.


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Recent Developments in Search of Antifilarial Agents
Rama Pati Tripathi, Diksha Katiyar, Namrata Dwivedi, Biswajit K. Singh and Jyoti Pandey

Filariasis, caused by spirunid nematodes, is one of the most prevalent diseases of tropical and subtropical countries and encompasses a number of different pathological conditions. It has great impact on the socioeconomic conditions of the people affected with this disease. The most common type of filariasis is a lymphatic filariasis caused by a parasite that lives in human lymph system. Like malaria, it is also caused by mosquito bites. The life cycle of the parasite, pathogenesis and diagnosis of filariasis have been briefly reviewed here in. Different strategies to control this disease have been discussed with major emphasis on the mechanisms, merits and demerits of the existing drugs and the drugs under pipeline. New antifilarial prototypes discovered recently and finally the future perspective to control the disease have also been elucidated.


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Bacteriocins as Oral and Gastrointestinal Antibiotics: Theoretical Considerations, Applied Research, and Practical Applications
B.C. Kirkup, Jr.

Bacteriocins, specific and highly potent protein antibiotics, have been long been expected to enter the working pharmacopeia. Despite laboratory experiments demonstrating their effectiveness against a wide range of gastrointestinal pathogens, attempts to reproduce such killing activity by using live bacteriocin-producing bacteria in animal gastrointestinal systems repeatedly failed. This raised doubts about the potential of the bacteriocins as in vivo antibiotics. Thus, though some bacteriocins have been employed in food preservation and processing, none have been applied directly as medicine. Recent experiments, based on an improved theoretical understanding of microbial ecology, demonstrate the in vivo activity of bacteriocins, the potential importance of bacteriocins as antibiotics, and the role that bacteriocins play in antibiotic resistance. Meanwhile, several kinds of bacteriocins have been proposed for applications in gastrointestinal microbiology, as well as for the use of probiotics to reduce dental caries and improve oral hygiene. Unfortunately, much of the probiotic-oriented research appears to be pursued without reference to resistance and the role of the bacteriocins in a community of bacteria. This leads to continued confusion regarding the interpretation of experimental results and mistaken assessments, positive and negative, of bacteriocins’ therapeutic potential. A study of microbial ecology should be incorporated in the drug development process in order to apply bacteriocins most effectively.


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Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research
Stefan Russmann, Ignazio Grattagliano, Piero Portincasa, Vincenzo O. Palmieri, and Giuseppe Palasciano

Ribavirin (RBV) is an antiviral nucleoside analogue commonly used in combination with interferon for the treatment of chronic hepatitis C. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and often RBV dose reduction, which may compromise sustained virologic response. Anemia is likely related to extensive RBV accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. RBV exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system. Concentration-dependent toxicity and improvement of anemia upon dose-reduction point towards the importance of pharmacokinetic factors for RBV-induced anemia. On the other hand, pronounced variability in the correlation between RBV concentration and Hb reduction limits the prediction of anemia based on plasma or erythrocyte concentrations in individual patients and points towards additional factors determining individual susceptibility to RBV-induced anemia. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia. Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Future research on RBV pharmacokinetics and pharmacodynamics, as well as erythrocyte antioxidant defense mechanisms may improve safety and efficacy of RBV therapy and guide the development of new treatments for RBV-induced anemia and alternative antiviral agents.