Current Pharmaceutical Design - Volume 12, Issue 22, 2006

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.......

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 αvβ3 integrin in order to block angiogenesis or osteoporosis, but there are also other integrins like αvβ5 and α5β1 which become more and more interesting for similar purposes. αIIbβ3 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 αvβ3 or αIIbα3, respectively. Additionally further advances in biomaterial research are presented. We describe the coating of different implant materials with various αvβ3 recognizing ligands for the purpose of increasing cell attachment and biocompatibility.

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 integrinmediated 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

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.

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 Tcell 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.

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.

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.

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 outcome 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.

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.