| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 22, 2006
Contents
Adhesion Molecules and Drug Targeting
Executive Editor: Seetharama D.S. Jois
Editorial Pp. 2721-2722
Targeting RGD Recognizing Integrins: Drug Development, Biomaterial
Research, Tumor Imaging and Targeting Pp. 2723-2747
A. Meyer, J. Auernheimer, A. Modlinger and H. Kessler
[Abstract]
Integrins in Drug Targeting-RGD Templates in Toxins
Pp. 2749-2769
X. Lu, D. Lu, M.F. Scully and V.V. Kakkar
[Abstract]
LFA-1 as a Key Regulator of Immune Function: Approaches
toward the Development of LFA-1-Based Therapeutics
Pp. 2771-2795
P.A. Giblin and R.M. Lemieux
[Abstract]
Targeting T-Cell Adhesion Molecules for Drug Design
Pp. 2797-2812
S.D.S. Jois, L. Jining and L.M. Nagarajarao
[Abstract]
Structure and Function of the Intercellular Junctions,
the Barrier of the Paracellular Drug Delivery Pp.
2813-2824
K. Zheng, M. Trivedi and T.J. Siahaan
[Abstract]
Leukocyte Adhesion: A Suitable Target for Anti-Inflammatory
Drugs Pp. 2825-2831
U. Mrowietz and W-H. Boehncke
[Abstract]
Adhesion Dependent Signalling in the Tumour Microenvironment:
The Future of Drug Targeting Pp. 2833-2848
M.A. Bewick and R.M. Lafrenie
[Abstract]
Adhesion Molecules as Targets for the Treatment
of Neoplastic Diseases Pp. 2849-2861
K.N. Syrigos and A.J. Karayiannakis
[Abstract]
Abstracts
[Back
to top]
Editorial
Adhesion Molecules and Drug Targeting
Cell adhesion molecules form a large group of proteins that
perform several functions. These adhesion molecules can be
broadly divided into families on the basis of their structure,
function and duration of cell-cell interactions. A majority
of adhesion molecules can be grouped into integrins, cadherins,
selectins and immunoglobulin superfamilies. Modulation of
cell adhesion is essential to inhibit tumor metastasis, suppress
the immune response in autoimmune diseases and for improving
drug delivery through biological barriers. Blocking the adhesion
molecular interaction or modulation of adhesion molecules
consequently produces biological effects of therapeutic value,
making adhesion molecules attractive candidates for drug-design.
Thus, the study of adhesion molecular interaction has been
an interest among several researchers around the world. The
fruitful efforts of research in this area are evident from
the approved drugs in the market. For example, Cilengitide,
an RGD based molecule targeting integrin has been developed
as an anti-angiogenesis agent.
Although, cell adhesion molecules were known for nearly two
decades, the details of their structure and function were
not well understood. During the past ten years 3D structures
of several adhesion molecules were elucidated and the modes
of interactions with their ligand were proposed. In this issue
of Current Pharmaceutical Design, we are bringing out eight
review articles on adhesion molecules by experts in this area.
These articles provide insight into the basic mechanisms of
protein-protein interactions at cell surface, the 3D structure
of the proteins as well as several ligands that were designed
for drug targeting, as imaging agents or as biomaterials.
The topics covered are at the interface of biotechnology,
structural biology and medicinal chemistry. Hence, it will
be of great interest to biologists, clinicians and pharmaceutical
scientists.
Among the cell adhesion molecules, integrins are well understood.
In the first article, Kessler and coworkers [1] discuss the
details of integrin targeting for drug design, biomaterial
and imaging. Special preference is given to state-of-the-art
structure function relationship and RGD-based ligands to target
the integrins. In another article, Lu and co workers [2] discuss
the RGD-based templates for toxins and drug design.
Another major integrin family receptors are Leukocyte Function
associated antigen (LFA) molecules expressed on T-cells. LFA-1
has been a target for drug design for several years. Its counter
receptor on the target cell is intercellular adhesion molecule
(ICAM-1). These molecules have been shown to be important
in autoimmune and inflammatory diseases.
In the article by Giblin and Lemieux [3], detailed structure
of LFA-1 and its interaction with ICAM-1 is discussed. Several
new and on going ligands of LFA-1/ICAM-1 as drug targets for
inflammatory and autoimmune diseases are presented. An article
by our group [4] (Jois and coworkers) discusses the possible
peptide ligands that are targeted to another set of adhesion
molecules CD2 and LFA-3.
Cadherins participate in structural integrity of cells and
form important barriers such as the blood-brain barrier. Siahaan
and coworkers [5] discuss the structural aspects of forming
these important junctions and possible drug targeting for
delivery of drugs across the blood-brain barrier.
Articles by Mrowietz and Boehncke [6]; Bewick and Lafrenie
[7]; Syrigos and Karayiannakis [8] cover the different adhesion
molecules and their importance in inflammatory diseases and
cancer.
There is no doubt that adhesion molecules are attractive targets
because of their importance in several stages of auto-immune
and inflammatory diseases and blood-brain barrier junctions.
The lead compounds and drug candidates described in this issue
represent novel compounds designed to treat several chronic
diseases. We hope that the articles presented in this issue
will provide a summary of the state-of-the-art in the drug
design area. These articles highlight the fact that research
on adhesion molecules spans across several key disciplines
including biotechnology, medicinal chemistry, structural biology
and rational drug design. Success in such multidisciplinary
research warrants close collaborations among clinicians, pharmaceutical
scientists and basic biologists. Indeed, such research endeavors
promise to yield several therapeutically useful agents in
the coming decade.
References
[1] Meyer A, Auernheimer J, Modlinger A, Kessler H. Targeting
RGD Recognizing Integrins: Drug Development, Biomaterial Research,
Tumor Imaging and Targeting. Curr Pharm Design 2006; 12(22):
2723-2747.
[2] Lu X, Lu, D, Scully MF, Kakkar VV. Integrins in Drug Targeting-RGD
Templates in Toxins. Curr Pharm Design 2006; 12(22): 2749-2769.
[3] Giblin PA, Lemieux RM. LFA-1 as a Key Regulator of Immune
Function: Approaches toward the Development of LFA-1-Based
Therapeutics. Curr Pharm Design 2006; 12(22): 2771-2795.
[4] Jois SDS, Liu J, Nagarajarao LM. Targeting T-cell Adhesion
Molecules for Drug Design. Curr Pharm Design 2006; 12(22):
2797-2812.
[5] Zheng K, Trivedi M, Siahaan TJ. Structure and Function
of the Intercellular Junctions, the Barrier of the Paracellular
Drug Delivery. Curr Pharm Design 2006; 12(22): 2813-2824.
[6] Mrowietz U, Boehncke WH. Leukocyte adhesion: A suitable
target for anti-inflammatory drugs? Curr Pharm Design 2006;
12(22): 2825-2831.
[7] Bewick MA, Lafrenie RM. Adhesion Dependent Signalling
in the Tumour Microenvironment: The Future of Drug Targeting.
Curr Pharm Design 2006; 12(22): 2833-2848.
[8] Syrigos KN, Karayiannakis AJ. Adhesion Molecules as Targets
for the Treatment of Neoplastic Diseases. Curr Pharm Design
2006; 12(22): 2849-2861.
Present Address:
Department of Basic Pharmaceutical Sciences
700 University Avenue
University of Louisiana
at Monroe, Monroe
LA 71209, USA
Tel: (318) 342-1993
Fax: (318) 342-1737
E-mail: jois@ulm.edu
Seetharama D.S. Jois
Assistant Professor
Department of Pharmacy, 18 Science Drive 4
National University of Singapore
Singapore 117543
Tel: 65-6516-2653
Fax: 65-6779-1554
E-mail: phasdsj@nus.edu.sg
[Back to top]
Targeting RGD Recognizing Integrins: Drug Development,
Biomaterial Research, Tumor Imaging and Targeting
A. Meyer, J. Auernheimer, A. Modlinger and H. Kessler
Integrins constitute an important class of cell adhesion receptors
responsible not only for cell-matrix adhesion but also for
signaling bidirectionally across the membrane. Integrins are
involved in many biological processes such as angiogenesis,
thrombosis, inflammation, osteoporosis and cancer. Integrins
thus play a key role in many severe human diseases. In this
review we will describe recent research and development of
RGD-containing integrin ligands for medical applications including
drug design, radiolabeling, drug targeting, as well as biomaterial
research.
Many ligands have been developed for targeting the αvβ
3 integrin in order to block angiogenesis or osteoporosis,
but there are also other integrins like αvβ
5 and α5β
1 which become more and more interesting for similar
purposes. αIIbβ
3 constitutes a potent target in thrombosis therapy;
but the search for suitable ligands is still ongoing. We will
reconstruct the drug development process for these integrin
subtypes considering selected examples with focus on structure
based design. Different structural requirements are pointed
out concerning integrin activity and particularly the selectivity
towards the distinct integrin types. Furthermore, we will
show recent progress in tumor and thrombosis imaging based
on radiolabeled RGD-containing ligands binding αvβ
3 or αIIbβ
3, respectively. Additionally further advances in biomaterial
research are presented. We describe the coating of different
implant materials with various αvβ
3 recognizing ligands for the purpose of increasing
cell attachment and biocompatibility.
[Back to top]
Integrins in Drug Targeting-RGD Templates in Toxins
X. Lu, D. Lu, M.F. Scully and V.V. Kakkar
Integrins are a family of heterodimeric receptors, which modulate
many cellular processes including: growth, death (apoptosis),
adhesion, migration, and invasion by activating several signaling
pathways. Integrin-binding RGD (arginine-glycine-aspartic
acid) is found in several important extracellular matrix proteins
which serve as adhesive integrin ligands. The RGD motif has
also been found in many toxins from snake venom and other
sources that specifically inhibit integrin binding function
and serve as potent integrin antagonists, particularly of
platelet aggregation and integrin-mediated cell adhesion.
Many of these proteins have potential as therapeutic agents
which can target integrins directly. Structural and functional
studies of several RGD-containing toxins suggest that the
inhibitory potency of these proteins lies in subtle positional
requirements of the tripeptide RGD at the tip of a flexible
loop, a structural feature for binding to integrins. In addition,
amino acid residues in this loop in close vicinity to the
RGD-motif determine the integrin-binding specificity and selectivity.
This review will present a review of integrin structure and
function, and of disintegrin structural features responsible
for their activity as antagonists of integrin function. The
use of integrins in drug targeting and integrins as targets
for drug delivery by using the RGD as a template structure
will also be discussed
[Back to top]
LFA-1 as a Key Regulator of Immune Function: Approaches
toward the Development of LFA-1-Based Therapeutics
P.A. Giblin and R.M. Lemieux
Over the past decade, Lymphocyte Function-Associated Antigen-1
(LFA-1, αLβ2,
CD11a/CD18) has emerged as an attractive therapeutic target
for the treatment of multiple inflammatory diseases. Its established
role in the trafficking and activation of leukocytes coupled
with the recent elucidation of the global conformational changes
that govern its function continue to drive pharmaceutical
interest in this target. This sustained interest has led to
the implementation of numerous drug discovery strategies leading
to the development of antibodies, peptidomimetics, and small
molecules that block LFA-1 function. The most successful demonstration
of clinical efficacy to date has been with Raptiva®,a
humanized anti-LFA-1 antibody. In clinical trials of patients
with moderate to severe psoriasis, improvements in several
disease specific parameters including the Psoriasis Area and
Severity Index (PASI) were observed. This review article will
provide an overview of LFA-1 biology and structural regulation,
as well as strategies that have been adopted in pursuit of
effective therapies. Recent findings with different classes
of small molecule antagonists will be highlighted with an
emphasis on how their different mechanisms of action on the
inserted domain (I domain) of CD11a have impacted our understanding
of LFA-1 function and illuminated other potential avenues
for therapeutic intervention.
[Back to top]
Targeting T-Cell Adhesion Molecules for Drug Design
S.D.S. Jois, L. Jining and L.M. Nagarajarao
Adhesion molecules participate in many stages of immune response;
they regulate leukocyte circulation, lymphoid cell homing
to tissues and inflammatory sites, migration across endothelial
cells and T-cell stimulation. During T-cell immune response,
adhesion molecules form a specialized junction between T-cell
and the antigen presenting cell. Thus, many researchers have
focused their attention on targeting adhesion molecules for
developing therapeutic agents. Most of these efforts are intended
to develop drugs for autoimmune and inflammatory diseases.
Therapeutic agents like efalizumab and alefacept have been
approved by the FDA for the treatment of inflammatory autoimmune
diseases. This review focuses on some of the basic aspects
and importance of adhesion molecules, recent understanding
of the structure of adhesion molecules, and the targeted therapeutic
agents.
[Back to top]
Structure and Function of the Intercellular Junctions,
the Barrier of the Paracellular Drug Delivery
K. Zheng, M. Trivedi and T.J. Siahaan
The delivery of large hydrophilic molecules (i.e.,
peptides and proteins) across biological barriers has been
hampered by the presence of tight junctions. This delivery
process can be improved by enhancing permeation through intercellular
junctions of the intestinal mucosa and blood-brain barriers.
This is achieved by modulating the intercellular junctions
of these biological barriers. To modulate intercellular junctions,
it is necessary to understand the structure and function of
the proteins that are involved in these junctions. This review
focuses on the structure of intercellular junctions and possible
mechanisms of intercellular junction formation. Modulation
of protein-protein interactions has been shown to increase
the porosity of the paracellular pathway. For example, E-cadherin
derived peptides have been shown to enhance the permeation
of hydrophilic molecules (i.e., mannitol) in cell
culture models of biological barriers.
[Back to top]
Leukocyte Adhesion: A Suitable Target for Anti-Inflammatory
Drugs
U. Mrowietz and W-H. Boehncke
Inflammatory responses in all tissue compartments require
the emigration of leukocytes from the microvasculature through
endothelial cells into the respective microenvironment. Adhesion
to endothelial cells is the most crucial step in order to
facilitate selective and effective capture of leukocytes.
The sequence of adhesions events, e.g. rolling, tethering,
and firm adhesion are tightly regulated by a variety of molecules
expressed by endothelial cells and leukocytes either constitutively
or after induction by mainly inflammatory mediators.
In diseases with a prominent inflammatory response such as
psoriasis, rheumatoid arthritis, or Crohn’s disease,
interference with leukocyte adhesion and/or emigration may
be of substantial clinical effect. A number of therapeutic
approaches by using monoclonal antibodies, designed molecules,
and other modulators of adhesion molecule expression have
been investigated in clinical trials. This review aims to
give an overview about the current knowledge of targeting
adhesion molecules as a therapeutic strategy to treat inflammatory
diseases.
[Back to top]
Adhesion Dependent Signalling in the Tumour Microenvironment:
The Future of Drug Targeting
M.A. Bewick and R.M. Lafrenie
Cellular adhesion molecules are critical components during
carcinogenesis and cancer metastasis and contribute to the
mechanisms underlying resistance to chemotherapeutic drugs.
Since drug resistance is associated with a very poor prognosis
for patients with cancer, a better understanding of the role
of adhesion molecules could improve patient out-come by identifying
novel mechanisms that promote drug resistance. Epigenetic
factors, such as cellular adhesion, are shown to promote the
resistance of cancers to various chemotherapeutic drugs by
altering cellular signalling pathways that activate cellular
growth and inhibit apoptosis. In addition, cellular adhesion
molecules can provide a means to specifically target more
conventional chemotherapy to the unique tumour microenvironment.
However, the expression and function of cellular adhesion
molecules, and the signals activated by adhesion, are highly
interrelated making the development of rational therapies
more difficult.
[Back to top]
Adhesion Molecules as Targets for the Treatment
of Neoplastic Diseases
K.N. Syrigos and A.J. Karayiannakis
The quest for therapeutic specificity is implicit
in all branches of medicine. In cancer treatment, cytotoxic
agents, such as chemotherapy and radiotherapy, comprise the
current therapeutic modality. Unfortunately, when used against
most solid malignancies, their therapeutic indices are relatively
low due to the significant damage they inflict on normal tissues.
Furthermore, cure rates have remained essentially static over
the last two decades. Specificity in killing neoplastic cells,
while sparing healthy ones is therefore the only alternative
approach, with several molecules qualifying as candidates
for targeting therapy. Reduction of cell-cell and cell-matrix
adhesion are, early tumorigenesis events also implicated in
the invasive and metastatic process. The fact that abnormal
adhesive marker expression is a feature commonly shared by
most malignancies, along with its tendency to occur as both
an early and late event in neoplastic development, makes these
molecules potential candidates for antineoplastic targeted
therapies. This review presents the perspectives of specific
anti-adhesion molecule targeting as a possible therapeutic
approach in neoplastic diseases.
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