Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 8, Number 1, January 2008

Contents


Proteomic Analysis of Liver Diseases: Molecular Mechanisms and Biomarker Discovery Pp. 1-9
Enrique Santamaría, Javier Muñoz, Joaquín Fernández-Irigoyen, Laura Sesma, Leticia Odriozola and Fernando J. Corrales
[Abstract]


Topiramate: Its Pharmacological Properties and Therapeutic Efficacy in Epilepsy Pp. 10-23
Giuseppe Latini, Alberto Verrotti, Rossella Manco, Alessandra Scardapane, Antonio Del Vecchio and Francesco Chiarelli
[Abstract]


Targeting the Viral Nucleocapsid Protein in Anti-HIV-1 Therapy Pp. 24-35
Hugues de Rocquigny, Volodymyr Shvadchak, Sergiy Avilov, Chang Zhi Dong, Ursula Dietrich, Jean-Luc Darlix and Yves Mély
[Abstract]


Bacterial β-Ketoacyl-Acyl Carrier Protein Synthase III (FabH): An Attractive Target for the Design of New Broad-Spectrum Antimicrobial Agents Pp. 36-45
Yunierkis Pérez Castillo and Miguel Ángel Cabrera Pérez
[Abstract]


Electrochemistry-Mass Spectrometry in Drug Metabolis and Protein Research Pp. 46-56
Hjalmar P. Permentier, Andries P. Bruins and Rainer Bischoff
[Abstract]


Protein Folding, Unfolding and Misfolding: Role Played by Intermediate States Pp. 57-62
R. Santucci, F. Sinibaldi and L. Fiorucci
[Abstract]


Essential Factors for Successful Virtual Screening Pp. 63-72
Markus H.J. Seifert and Martin Lang
[Abstract]


Current Status of COX-2 Inhibitors Pp. 73-90
Palwinder Singh and Anu Mittal
[Abstract]


The Adipocyte as a Novel TSH Target Pp. 91-96
A. Sorisky, T.T. Antunes and A. Gagnon
[Abstract]



Abstracts


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Proteomic Analysis of Liver Diseases: Molecular Mechanisms and Biomarker Discovery
Enrique Santamaría, Javier Muñoz, Joaquín Fernández-Irigoyen, Laura Sesma, Leticia Odriozola and Fernando J. Corrales

Liver diseases afflict more than 10% of the world population. Although the main risk factors are known and the population at risk is monitored, new biomarkers are urgently needed to allow early diagnosis and hence more effective therapeutic interventions. Here, we revise the contribution of proteomics to the study of liver diseases and its potential impact in the clinical practice is evaluated.


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Topiramate: Its Pharmacological Properties and Therapeuti Efficacy in Epilepsy
Giuseppe Latini, Alberto Verrotti, Rossella Manco, Alessandra Scardapane, Antonio Del Vecchio and Francesco Chiarelli

Since 1990 eight new antiepileptic drugs (AEDs) have been developed. Among these new drugs, Topiramate (TPM) is one of the latest AEDs available for treating drug resistant partial epilepsy both in adults and in children. The mechanisms underlying TPM antiepileptic activity are still incompletely understood. However, TPM, a sulfamate-substituted derivative of the naturally occurring monosaccharide D-fructose, has a different structure from other known AEDs. The antiepileptic activity of TPM in animal models of partial and generalized tonic-clonic seizures has been shown to be more effective as compared to other AEDs. Proposed mechanisms of action include reduction of epileptiform discharges through a voltage-dependent block of Na⁺ channels, enhancement of the activity of γ-aminobutyrate at some subtypes of γ-aminobutyrate receptors, and antagonism of non- N-methyl-D-aspartate (NMDA) glutamate receptors. The pharmacokinetic profile of TPM, which is characterized by its rapid and almost complete absorption after oral administration, linear pharmacokinetics, minimal protein binding and predominantly renal excretion, makes the drug a good option for the treatment.

TPM was found to be effective and well tolerated in many studies conducted in adults and pediatric patients suffering from epilepsy.

This review, summarising the main studies in this field, provides an overview of the current knowledge about the relevant pharmacological and clinical information on the efficacy and tolerability of TPM.


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Targeting the Viral Nucleocapsid Protein in Anti-HIV-1 Therapy
Hugues de Rocquigny, Volodymyr Shvadchak, Sergiy Avilov, Chang Zhi Dong, Ursula Dietrich, Jean-Luc Darlix and Yves Mély

The nucleocapsid protein (NC) plays seminal roles in HIV replication, thus representing a major drug target. NC functions rely on its two zinc-fingers and flanking basic residues. Zinc ejectors inhibit NC functions, but with limited specificity. New classes of molecules competing with NC or its viral nucleic acid and enzyme partners are reviewed here.


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Bacterial β-Ketoacyl-Acyl Carrier Protein Synthase III (FabH): An Attractive Target for the Design of New Broad-Spectrum Antimicrobial Agents
Yunierkis Pérez Castillo and Miguel Ángel Cabrera Pérez

The emergence of drug resistant strains of important human pathogens has made urgent the necessity of finding new targets and novel antimicrobial agents. One of the most promising targets is FabH. In this review we summarize the progress made in the design of FabH inhibitors and the role played by the 3D-structure of the enzyme in the drug design process.


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Electrochemistry-Mass Spectrometry in Drug Metabolism and Protein Research
Hjalmar P. Permentier, Andries P. Bruins and Rainer Bischoff

The combination of electrochemistry coupled on-line to mass spectrometry (EC-MS) forms a powerful analytical technique with unique applications in the fields of drug metabolism and proteomics. In this review the latest developments are surveyed from both instrumental and application perspectives. The limitations and solutions for coupling an electrochemical system to a mass spectrometer are discussed. The electrochemical mimicking of drug metabolism, specifically by Cytochrome P450, is high-lighted as an application with high biomedical relevance. The EC-MS analysis of proteins also has promising new applications for both proteomics research and biomarker discovery. EC-MS has furthermore advantages for improved analyte detection with mass spectrometry, both for small molecules and large biomolecules. Finally, potential future directions of development of the technique are briefly discussed.


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Protein Folding, Unfolding and Misfolding: Role Played by Intermediate States
R. Santucci, F. Sinibaldi and L. Fiorucci

Most proteins fold into their native structure through well defined pathways which involve a limited number of transient intermediates. Intermediates play a relevant role in the folding process; many diseases of genetic nature are in fact coupled with protein misfolding due to formation of stable, inactive intermediate species of the protein. This review deals with a number of diseases associated with protein misfolding and briefly describes the mechanism(s) responsible, at molecular level, for such pathologies. It is also considered the (native molten globule) transition, recently observed for some proteins, in which a native protein converts into a stable compact intermediate state able to carry out distinct physiological functions inside the cell. A non-native compact form of cyt c, for example, appears to have a role in the programmed cell death (apoptosis) after that the protein is released from the mitochondrion, and non-native forms of the same protein appear involved in some of the disorders attributed to amyloid formation.


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Essential Factors for Successful Virtual Screening
Markus H.J. Seifert and Martin Lang

Virtual high-throughput screening (vHTS) is a powerful technique for identifying hit molecules as starting points for medicinal chemistry. Numerous successful applications of vHTS have been published using a large variety of methodologies. This review attempts to identify the essential factors for successful virtual screening in the hit identification phase.


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Current Status of COX-2 Inhibitors
Palwinder Singh and Anu Mittal

The two isoforms of enzyme cyclooxygenase viz. COX-1 and COX-2 play key roles in the metabolism of arachidonic acid. The enzyme COX-2, when over expressed, leads to more production of prostaglandins causing inflammation and it also participates in the propagation of cancer. Therefore, COX-2 becomes the cellular target of a number of chemical entities for the treatment of inflammatory diseases as well as for the chemotherapy of cancer.

In the present review, an up to date status of the compounds investigated for COX-2 inhibition has been given so that a collective view of the existing COX-2 inhibitors could be helpful for the design of safer anti-inflammatory drugs. In order to cover the maximum reported COX-2 inhibitors, a unique classification on the basis of the central core of the molecule (carrying mostly the phenyl moieties) has been followed, an outline of which has been given below:



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The Adipocyte as a Novel TSH Target
A. Sorisky, T.T. Antunes and A. Gagnon

Thyroid stimulating hormone (TSH; also known as thyrotropin), binds cognate receptors on the surface of thyrocytes to regulate proliferation and thyroid hormone synthesis. This unidimensional view of TSH is being transformed as new evidence indicates that TSH acts on adipose tissue. Adipocyte inflammatory responses that predispose to cardiovascular disease may occur in thyroid disorders associated with elevated TSH levels.