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Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 2, Number 4, November 2006
Contents
Regular Papers
Computer-Aided Drug Design Applied to Beta
and Gamma Secretase Inhibitors-Perspectives for New Alzheimer
Disease Therapy Pp. 311-328
Speranta Avram, Adina L. Milac, Dan F. Mihailescu, Aurelia
Dabu and Maria L. Flonta
[Abstract]
Sesquiterpene Lactones as a Potent Class of NF-κB
Activation Inhibitors Pp. 329-341
Jae Youl Cho
[Abstract]
Inhibitors of Laccases: A Review Pp.
343-352
Susana R. Couto and José L. Toca
[Abstract]
Inhibiting the Enzymes of the Endothelin and Renin-Angiotensin
Systems in Cancer Pp. 353-362
Lucienne Juillerat-Jeanneret
[Abstract]
Non-Specific Effects of Exogenous Compounds on Bacterial
Bioluminescent Enzymes: Fluorescence Study Pp. 363-372
Nadezhda S. Kudryasheva
[Abstract]
Endothelin-Converting Enzyme Inhibitors
Pp. 373-378
Cristina Navarrete and Cleide Suguihara
[Abstract]
Superoxide Dismutases and Their Inhibitors–the
Role in Some Diseases Pp. 379-397
[Abstract]
Abstracts
[Back to top]
Computer-Aided Drug Design Applied to Beta and Gamma
Secretase Inhibitors-Perspectives for New Alzheimer Disease
Therapy
Speranta Avram, Adina L. Milac, Dan F. Mihailescu, Aurelia
Dabu and Maria L. Flonta
Alzheimer’s disease (AD) is characterized
by the presence of extracellular amyloid plaques, containing
the extracellular amorphous deposits of beta-amyloid protein
and intracellular neurofibrillary tangles, comprising filaments
of phosphorylated form of a microtubule-associated protein
Tau, localized in the brain. It is considered that the major
constituent of amyloid plaques, beta-amyloid peptide (Aβ),
induces AD neuropathology. AD enzymatic pathway comprises
several events: (i) beta-secretase cleaves amyloid precursor
protein (APP) and releases a soluble fragment, beta-APPs,
and (ii) gamma-secretase cleaves the C-terminal membrane bound
C99 peptide within the transmembrane domain, thus generating
two major amino acid isoforms of beta-amyloid: Aβ40
and Aβ42.
This review is focused on the recent advances in the field
of computational chemistry (molecular docking, 3D-QSAR (CoMFA
(Comparative Molecular Field Analysis) and CoMSIA (Comparative
Molecular Similarity Indices Analysis)), molecular dynamics
and rational drug design) applied to inhibitions of beta and
gamma secretases. Computational chemistry studies have been
performed for different inhibitors of beta and gamma secretases
(e.g. benzodiazepine, urethane and tetrapeptide derivatives)
resulting in their predicted biological activities and free
energies.
[Back to top]
Sesquiterpene Lactones as a Potent Class
of NF-κB
Activation Inhibitors
Jae Youl Cho
Sesquiterpene lactones (SLs) are biologically
active compounds found in various medicinal plants. Although
the compounds are reported to possess numerous biological
activities, but the most important is their immunoregulatory
role in inflammatory cells. This is because 1) over-activation
of inflammatory cells secretes a large amount of different
pro-inflammatory mediators such as cytokines, nitric oxide
(NO) and prostaglandin (PG)E2 and 2) SLs can modulate
these phenomena effectively through inhibiting the activation
pathway of nuclear factor (NF)-κB
via the reactivity of some functional groups in SLs
such as α-methylene-γ-lactone.
This review, therefore, discusses in detail the molecular
mechanism and structural features of SLs in blocking NF-κB
activation with a general introduction of NF-κB
and proposes the possibility that SLs can be developed pharmaceutically
useful drugs against NF-κB-mediated
diseases and that they can be chemically modified to improve
their anti-NF-κB
efficacy.
[Back to top]
Inhibitors of Laccases: A Review
Susana R. Couto and José L. Toca
Laccases are an interesting group of multicopper
enzymes, which have received much attention of researchers
in last decades due to their ability to oxidise both phenolic
and non-phenolic lignin-related compounds as well as highly
recalcitrant environmental pollutants. This makes these biocatalysts
very useful for their application to several biotechnological
processes. Soil and water contamination is often accompanied
by several organic and inorganic compounds. Therefore, it
is important to know the stability of laccases under the conditions
present in such environments, since it can influence the effectiveness
of the bioremediation technologies. Recently, the utility
of laccases has also been applied to Nanobiotechnology. This
is an increasing research field mainly due to the fact that
laccases are able to catalyse electron transfer reactions
without additional cofactors and to the development of several
techniques for the immobilisation of biomolecules such as
micropatterning, self-assembled monolayers and layer-by-layer
technique. These techniques can be used to immobilise laccases
preserving their enzymatic activity. This paper reviews the
effect of the potential laccase inhibitors that can be found
in polluted environments on laccase activity.
[Back to top]
Inhibiting the Enzymes of the Endothelin
and Renin-Angiotensin Systems in Cancer
Lucienne Juillerat-Jeanneret
The renin-angiotensin (RAS) and endothelin/ET-1,-2,-3
systems comprise families of precursor peptides, angiotensinogen
and big-endothelins respectively, activated by families of
proteases. Angiotensinogen is activated by the sequential
action of an aspartyl-protease, renin, then a metalloprotease,
angiotensin converting enzyme (ACE). Big-endothelins are activated
by the metalloproteases endothelin converting enzyme/ECE-1a-d,
and to a lesser extent neprilysin (NEP/CD10). These proteolytic
cascades produce the system-representative active peptides
angiotensin II (Ang II) and endothelin-1 (ET-1). Then several
exopeptidases, which include aminopeptidases or carboxypeptidases,
and endopeptidases, in particular NEP, further process these
active peptides to either inactive fragments or intermediate
peptides with various biological activities. The RAS and ET
systems have been mainly studied in the context of cardiovascular
disorders, and either agonists or antagonists of their receptors,
and inhibitors for the enzymes metabolizing the precursors
and/or the active peptides have been developed for the treatment
of these disorders. However, the RAS and ET systems, in addition
to controlling the vascular tone and natriohydric balance,
may be involved in cell growth and/or death in cancer, fibrotic
or degenerative diseases. Therefore the protease inhibitors
developed for treating cardiovascular disorders may have wider
application in cancer than initially envisioned, which will
be reviewed in this manuscript
[Back to top]
Non-Specific Effects of Exogenous Compounds
on Bacterial Bioluminescent Enzymes: Fluorescence Study
Nadezhda S. Kudryasheva
A study of influence of exogenous (xenobiotic)
molecules on enzymatic reactions provides a basis for prediction
and interpretation of effects of toxic compounds on metabolic
processes in complex organisms. A coupled system of two enzymatic
reactions catalyzed by luciferase and NAD(P)H:FMN-oxidoreductase
from luminous bacteria Photobacterium phosphoreum
is considered as a simple model of a living organism. Three
main mechanisms of xenobiotics’ influence are: (1) change
of electron-excited states population in a bioluminescent
emitter; (2) change of rates of the coupled reactions; and
(3) interactions with the enzymes. The paper mainly deals
with the third case. The results of impacts of different molecular
groups (fluorescent dyes, organic oxidizers, and haloid compounds)
are summarized. Binding of the compounds with the enzymes
is tracked through time-resolved fluorescence techniques.
Results of an indirect fluorescent method for studying interactions
of nonfluorescent compounds (quinones) with the enzymes are
discussed. Correlations between physico-chemical characteristics
of exogenous compounds (hydrophobicity or atomic weight of
haloid substituents) and efficiency of their interactions
with the enzymes are demonstrated.
[Back to top]
Endothelin-Converting Enzyme Inhibitors
Cristina Navarrete and Cleide Suguihara
Endothelin-1 (ET-1) is a peptide with various biological
activities, such as vasoconstriction, mitogenesis and bronchoconstriction.
It has been implicated in the pathogenesis of numerous disease
processes. Suppression of the production of this peptide by
inhibitors of endothelin-converting enzyme-1 (ECE-1), the
key enzyme in ET-1 biosynthesis, may be a therapeutic option.
There are three classes of ECE-1 inhibitors: selective ECE-1
inhibitors, dual ECE-1/neutral endopeptidase (NEP) 24.11 inhibitors
and triple ECE-1/NEP/angiotensin-converting enzyme inhibitors.
This review will focus briefly on the endothelin system and
mainly on the ECE-1 inhibitor classes, their pharmacologic
effects on animal models of various diseases and published
clinical studies.
[Back to top]
Superoxide Dismutases and Their Inhibitors–the
Role in Some Diseases
Superoxide dismutase (SODs, E.C.1.15.1.1) are metalloproteins,
which are subdivided into four different catagories, as they
contain different metals: copper/zinc (Cu/Zn) superoxide dismutase,
manganese (Mn) superoxide dismutase, iron (Fe) superoxide
dismutase, and nickel (Ni) superoxide dismutase. In mammalian
tissues, due to location in cell, dismutases are divided into
cytosolic dismutase - CuZnSOD (SOD-1) that is present in cytoplasm
and nucleus, mitochondrial dismutase - MnSOD (SOD-2) that
is contained in mitochondrial matrix, and extracellular dismutase
- EC-SOD (SOD-3) that exists in intracellular spaces of tissues
and extracellular fluids (plasma, lymph, celebral-modulatory
or synovial). SODs eliminate superoxide radicals from cell
environment and prevents formation of reactive oxygen species
and their derivatives. SODs are characterized by thier peroxidative
activity: they degrades hydrogen peroxide at the participation
of uric acid, HCO3- and other substrates such as
formate, glutamate, tyrosine, etc. Superoxide dismutases may
be only damaged by some xenobiotics, e.g., azide, cyanides,
chloric acid or diethyl-dithio-carbamate and hydrogen peroxide.
They play an essential role in stabilization of blood pressure
and correct astrocytes blood supply. They are responsible
for male fertility, lung function, NO metabolism, and also
for development of numerous diseases. In this review, we describe
the effect of age and some physical (ionization) and chemical
factors (hydrogen peroxide, 2-methoxyestradiol, diethyl-dithio-carbamate,
chlorophenols, 2,3,7,8-tetrachloro-dibenzo-p-dioxin, microcystin-LR)
on the activity of SODs. As their activity is decreased in
many diseases and under influence of many physical and chemical
factors, it is supposed that SOD supplementation may be very
important in therapy. Administration of recombined EC-SOD
may prevent cells from damages caused by radical activity.
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