The
Therapeutic Potential for Catalytic Antibodies: From a Concept to a
Promise Pp. 125-132
Lyn H. Jones and Paul Wentworth, Jr.
Leucine
Aminopeptidase as a Target for Inhibitor Design. Pp. 133-144
J. Grembecka and P. Kafarski
Therapeutic Applications of Sugar-Mimicking Glycosidase Inhibitors Pp. 145-154
Naoki Asanoa, Atsushi Kato and Alison A.
Watson
Origin
of Chiral Pharmacology: Stereochemistry in Metalloprotease Inhibition Pp.
155-161
D. H. Kim
Tacrine-Huperzine
A Hybrids (Huprines): A New Class of Highly Potent and Selective
Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's
Disease Pp. 163-174
P. Camps and D. Muñoz-Torrero
b-Amyloid Aggregation Inhibitors for the
Treatment of Alzheimer’s Disease: Dream or Reality? Pp. 175-186
Patrice Talaga
Quantitative
Structure-Activity Relationship (QSAR) Paradigm – Hansch Era to New Millennium Pp.
187-195
Asim Kumar Debnath
Pharmaceutical
Target Identification by Gene Expression Analysis Pp. 197-205
Michael G. Walker
Antihypertensive
Drugs that Act on Renin-Angiotensin System with Emphasis in AT1 Antagonists Pp.
207-217
T. Mavromoustakos, V. Apostolopoulos, and
J. Matsoukas
[Back to top] The Therapeutic Potential for Catalytic
Antibodies: From a Concept to a Promise
More than ten years have now elapsed since the first reports confirmed that antibodies not only label antigenic targets but can also perform catalytic functions. Much of the initial research in this area focussed on exploring the scope and utility of these biocatalysts both as enzyme mimics and as programmable protein catalysts. However, their potential in the biomedical field has also been probed. This review details the present perspective of catalytic antibodies as new tools for immunotherapy and specifically focuses on their application to prodrug activation and drug inactivation.
[Back to top] Leucine Aminopeptidase as a Target for
Inhibitor Design.
In
this review we focus on the most effective and the most promising inhibitors of
leucine aminopeptidase. Their binding modes to the enzyme, the attempt to
explain the origin of the inhibitory activity, as well as the structure –
activity relationship for some of these compounds are discussed. Besides, the
structural and electronic requirements of the enzyme active site and the
binding pockets, together with the specificity towards the ligands, based on
the structural and kinetic data, are presented.
.
[Back to top] Therapeutic Applications of Sugar-Mimicking Glycosidase Inhibitors
Sugar-mimicking
alkaloids inhibit the glycosidases involved in a wide range of important
biological processes, principally owing to their structural resemblance to the
sugar moiety of the natural substrate. The possibility of modifying and
blocking these processes by using such inhibitors for therapeutic applications
has attracted a lot of attention.
[Back to top] Origin of Chiral Pharmacology:
Stereochemistry in Metalloprotease Inhibition
The
stereospecificity shown by a wide variety of inhibitors that are effective for
carboxypeptidase A (CPA), a representative zinc protease is analyzed on the
basis of inhibitor type. In cases of ground state analog inhibitors and
transition state analog inhibitors, the stereoisomers having the
stereochemistry that corresponds to stereochemistry of substrate are more
potent, but in the case of irreversible inhibitors including mechanism-based
inactivators the preferred inhibitory stereochemistry cannot be predicted
simply from the substrate stereospecificity. The Ogston’s three point fit
concept may be of great value in understanding the inhibitory stereochemistry
of reversible competitive inhibitors. On the other hand, the stereochemistry of
irreversible inhibitors may possibly be predicted on the ground of the
transition state structure that plays a critical role in the inactivation
pathway.
.
[Back to top] Tacrine-Huperzine A Hybrids (Huprines): A
New Class of Highly Potent and Selective Acetylcholinesterase Inhibitors of
Interest for the Treatment of Alzheimer's Disease
P. Camps and
D. Muñoz-Torrero
Tacrine-huperzine
A hybrids (huprines) are a new class of very potent and selective
acetylcholinesterase (AChE) inhibitors. Huprines were designed from tacrine and
(-)-huperzine A through a conjunctive approach. They combine the
4-aminoquinoline substructure of tacrine with the carbobicyclic substructure of
(-)-huperzine A. Structural variations on several parts of a lead structure
have allowed to complete a structure-activity relationship exploration of this
new structural family and have led to several huprines more active than other known
AChE inhibitors.
[Back to top] b-Amyloid
Aggregation Inhibitors for the Treatment of Alzheimer’s disease: Dream or
Reality?
Amyloid
(Ab) deposition remains a hallmark in the pathology
of Alzheimer’s disease (AD). Academic groups and the pharmaceutical industry as
a potential preventive treatment for AD pursue important drug discovery efforts
dedicated to the inhibition of the polymerization process leading to amyloid
neurotoxicity. The aim of this review is to up-date current knowledge on the
amyloid aggregation process and the various available peptidic and non-peptidic
Ab aggregation inhibitors.
[Back to top] Quantitative Structure-Activity Relationship
(QSAR) Paradigm – Hansch Era to New Millennium
The
analysis of structure-activity relationships started probably more than hundred
years ago but the concept of quantitatively correlating physicochemical
properties of molecules with their biological activities, termed as
quantitative structure-activity relationship (QSAR), was initiated by Corwin
Hansch and his groups in early 1960. Many new methods have emerged since then.
The concept evolved from 2D QSAR to 3D QSAR and lately another dimension (4D
QSAR) has been added. This evolution is briefly reviewed here.
[Back to top] Pharmaceutical Target Identification by Gene
Expression Analysis
The majority of newly identified genes in the human genome show no
significant sequence similarity to genes whose function is known, so they are
not easily recognized as potential drug targets. Expression analysis is an
alternative method to suggest possible functions of genes. We review
statistical methods for gene expression analysis to identify potential
pharmaceutical targets. Specifically, we illustrate the analysis of
differential gene expression (using discriminant analysis, t-tests, and
analysis of variance) and co-expression (using correlation, clustering, and
chi-square). We present an example of the use of expression analysis to
identify co-expressed cardiomyopathy-associated genes.
[Back to top] Antihypertensive Drugs that Act on
Renin-Angiotensin System with Emphasis in AT1 Antagonists
Angiotensin II, the primary
active hormone in the Renin-Angiotensin System is a major vasoconstrictor
implicated in the cause of hypertension.
Research efforts have focused in the treatment of disease by blocking
its release and more recently by competing its action on AT1
receptors. This approach generated in the pharmaceutical market, losartan, and
other derivatives. To better understand the stereoelectronic requirements that
lead to the molecular basis of hypertension the stereochemical features of
angiotensin II and its antagonists are studied.