Mini-Reviews in Medicinal Chemistry, Volume 2, No. 4, 2002
Biomembrane Permeability of Peptides: Strategies to
Improve Their Mucosal Uptake
Pp.295-305
Andreas
Bernkop-Schnürch and Andreas E. Clausen
Cell Membranes As
Barriers for The Use of Antisense Therapeutic Agents Pp.307-318
Ilpo Jääskeläinen and Arto Urtti
Liposomes for Intravenous Drug Targeting: Design and
Applications Pp.319-329
Josbert M. Metselaar, Enrico Mastrobattista and Gert Storm
Membranes as Targets
for Drug Design
How Do Channel- and Pore-Forming Helical
Peptides Interact with Lipid Membranes and How does this Account for their Antimicrobial Activity? Pp.331-342
Hervé Duclohier
The Biochemical and Physiological
Characteristics of Surface Receptors of Gram Negative Bacteria Pp.343-351
Lucienne Letellier and Mónica Santamaria
Cytosolic Calcium Oscillations in Signal Transduction
Pathways Pp.353-360
Michel
F. Rossier and Alessandro M. Capponi
Heterotrimeric G Proteins Control Diverse Pathways of Transmembrane Signaling, a Base for Drug Discovery Pp.361-372
Yves
Landry and Jean-Pierre Gies
Structure, Function and Modulation of Chemokine Receptors: Members of the G-Protein-Coupled
Receptor Superfamily Pp.373-383
Ziwei Huang
Molecular and Physicochemical Aspects of
Local Anesthetics Acting on
Nicotinic Acetylcholine Receptor-containing Membranes Pp.385-410
Hugo
R. Arias and Michael P. Blanton
Non-genomic Effects of Steroid Hormones on
Membrane Channels Pp.411-417
Jean-Claude
Hervé
Nerve Membrane Ion Channels as the Target
Site of Insecticides Pp.419-432
Toshio Narahashi
[Back to top] Biomembrane Permeability of Peptides: Strategies to
Improve Their Mucosal Uptake
Andreas
Bernkop-Schnürch and Andreas E. Clausen
In order to gain a therapeutic response after mucosal
administration peptide drugs have to permeate the absorption membrane based on
the mucus layer (I) and the epithelial tissue (II ) in
significant quantities.The peptide drug transport across the membrane
can be improved by the use of mucolytic agents and
the permeation enhancers. The generation of novel, more potent permeation
enhancers, based on an improved knowledge of the absorption membrane in
combination with the appropriate delivery systems will strongly improve the bioavailability of mucosally applied peptide drugs.
[Back to top] Cell Membranes As
Barriers for The Use of Antisense Therapeutic Agents
Ilpo Jääskeläinen and Arto Urtti
Antisense oligonucleotides
are promising therapeutical agents for numerous
diseases resulting from overexpression of genes,
expression of mutant genes and viral infections. As most oligonucleotides
are polyanions they can not readily pass cellular
membranes in adequate amounts to show activity. Therefore, different types of
carrier systems and modifications have been developed to enhance absorption and
distribution at the level of tissues and cells. The current state of delivery
systems will be reviewed with a major part devoted to the commonly used
cationic lipids.
[Back to top] Liposomes for Intravenous Drug Targeting: Design and
Applications
Josbert M. Metselaar, Enrico Mastrobattista and Gert Storm
Drug targeting
with liposomes has been studied for over 25 years and
has demonstrated its value in clinical practice. This mini review offers an
overview of the design and application of liposomes
for i.v. drug targeting. Two approaches are outlined:
passive and active targeting. The former approach is based on liposomes with prolonged circulation and selective target
localization properties, while in the latter approach specific targeting ligands are coupled to the liposome surface in order to
achieve enhanced interaction with target cell membranes.
[Back to top] How Do Channel- and Pore-Forming Helical Peptides Interact with
Lipid Membranes and How does this Account for their Antimicrobial Activity?
Hervé Duclohier
Animals and plants
defend themselves against pathogenic micro-organisms by the rapid mobilization
of polycationic helical amphipathic
peptides. Interactions with membranes induce optimal orientation and mutual
structural changes, allowing for example to form transbilayer
ion channels or pores whose properties are compared in this review.
Physicochemical studies of peptide-lipid interactions provide attractive
approaches for drug design.
[Back to top] The Biochemical and Physiological
Characteristics of Surface Receptors of Gram Negative Bacteria
Lucienne Letellier and Mónica Santamaria
This review
focuses on the properties of ferric iron surface receptors of Gram negative
bacteria. We discuss the different strategies to acquire iron, and the
fundamental role of these receptors in pathogenicity.
The structure of some of these receptors, iron transport and regulation
mechanisms are presented here.
[Back to top] Cytosolic Calcium Oscillations in Signal Transduction
Pathways
Michel
F. Rossier and Alessandro M. Capponi
The oscillatory
nature of the intracellular calcium signal has been recognized as soon as the
methodological developments allowed us to record calcium fluctuations at the
single cell level. While the principal mechanisms responsible for the
generation of these oscillations have been partially resolved, more attention
has been recently focused on signal decoding and more particularly on the role
of cell structure organization in transducing this
signal to the molecular targets of the calcium messenger.
[Back to top] Heterotrimeric G Proteins Control Diverse Pathways of Transmembrane Signaling, a Base for Drug Discovery
Yves
Landry and Jean-Pierre Gies
Heptahelical receptors are coupled to heterotrimeric
GTP-binding proteins (G proteins) which transduce most signals through their a and bg
subunits to effectors including adenylylcyclases, ion
channels, phospholipases Cb, and phosphoinositide
3-kinases. The diversity of G
proteins, their effectors and regulators (RGS proteins),
supports the interest of these protein families as potential drug targets.
[Back to top] Structure, Function and Modulation of Chemokine Receptors: Members of the G-Protein-Coupled
Receptor Superfamily
Ziwei Huang
Chemokine receptors are membrane proteins that play an
important role in inflammation and the cellular entry of human immunodeficiency
virus type I (HIV-1). Understanding the structure-function relationship of chemokine receptor-ligand
interactions and developing novel strategies to control these interactions have
important implications for therapeutic intervention of human diseases such as
HIV-1 infection. This article reviews the work carried out in our laboratory in
molecular modeling and site-directed mutagenesis of chemokine
receptor-ligand interactions and chemical synthesis
of chemokine-derived peptide agonists and
antagonists. These studies demonstrate a paradigm for exploring and controlling
membrane protein-protein interactions.
[Back to top] Molecular and Physicochemical Aspects of
Local Anesthetics Acting on
Nicotinic Acetylcholine Receptor-containing Membranes
Hugo
R. Arias and Michael P. Blanton
Local anesthetics
inhibit the ion channel activity of nicotinic acetylcholine receptors in a
noncompetitive fashion. This inhibitory action is ascribed to two possible
inhibitory mechanisms: an openchannel- blocking
mechanism and/or an allosteric process where the drug
binds either to the closed channel or to other nonluminal
sites, respectively.
[Back to top] Non-genomic Effects of Steroid Hormones on
Membrane Channels
Jean-Claude
Hervé
Steroid hormones
may possess two distinct actions, a delayed genomic influence and the rapid nongenomic effects, which may act in concert. Nongenomic effect may be mediated by putative membrane
receptors or due to allosteric interactions of
steroids with membrane proteins (e.g. ionic channels), inducing rapid changes
in protein/receptor/channel activation or inhibition.
[Back to top] Nerve Membrane Ion Channels as the Target
Site of Insecticides
Toshio
Narahashi
Most insecticides
are potent neurotoxicants that act on various neuroreceptors and ion channels.However, the major
target receptors are limited to sodium channels, GABA
receptors, and nicotinic acetylcholine receptors. DDT and pyrethroids
act similarly on sodium channels to keep them open leading to hyperexcitation. Indoxacarb
inhibits sodium channels and certain subtypes of nicotinic receptors. Dieldrin,lindane and fipronil block GABA receptors. Imidacloprid modulates nicotinic receptors in a complex
manner. Spinosad’s major target site appears to be
nicotinic receptors.