Drug Design Reviews - Online (Discontinued) - Volume 2, Issue 3, 2005

Although the regulation of cellular processes is mediated to a large extent by posttranslational modification of proteins, the target specificity of enzymatic, e.g. protein kinase and phosphatase, activities derives in large part from protein-protein interactions (PPIs) rather than enzyme substrate specificity. Similarly, signal transduction through interaction of biological effectors such as hormones and cytokines with their receptors is mediated by PPIs. For this reason PPIs represent attractive targets for modern mechanism based drug design. PPIs have been more difficult to modulate pharmacologically with drug-like small molecules than catalytic sites, however. The reasons for this apparent lack of success with PPI inhibitors are discussed here and new insights into the requirements for effective PPI modulation from both the ligand and receptor viewpoints are summarised. In particular, the emerging concept of protein plasticity and its implications for drug discovery and design are introduced. Recent breakthroughs with drug-like small molecules targeting PPIs are presented as a series of case studies in order to illustrate modern concepts and peptidomimetic techniques that will hopefully result in the development of a new generation of disease mechanism based PPI modulator drugs.

Since the time of the earliest jawed fish, some 400 million years ago, evolution has been honing the design of antibody molecules to function as specific markers, alerting immune defences to the presence of pathogenic antigens, and recruiting effector function in the form of complement and Fc receptor-bearing cells. For the last twenty-five years, the biopharmaceutical industry has been applying the versatility of antibodies to the treatment of disease, with roles ranging from the blocking of receptor/ligand interactions to the delivery of cytotoxic drugs. While the structures of antibody molecules are supremely tailored to carry out their natural roles, there is considerable scope for adapting the basic designs to match more closely the specific requirements now sought for antibodies as drugs. In this review, we chart the developments in antibody design, which have led to successful therapies, highlighting the key issues and challenges faced, and looking to a future in which antibody-based therapies will represent a significant proportion of newly registered products.

Mast cells are multifunctional effector cells of the immune system, capable of producing a variety of vasoactive mediators, cytokines and growth factors. The presence of resident mast cells in the myocardium has been established; however, their exact role in cardiac pathology remains unclear. The current review presents evidence suggesting the importance of mast cells in the infarcted myocardium. Myocardial ischemia and reperfusion results in degranulation of cardiac mast cells, and release of preformed inflammatory mediators, such as TNF-α and histamine in the ischemic area. Mast cell derived products may modulate endothelial gene expression and mononuclear cell cytokine synthesis. During the proliferative phase of healing, significant mast cell accumulation is noted in areas of fibrosis and myofibroblast proliferation. Stem Cell Factor (SCF), the obligate growth factor for mast cells, is induced in the healing myocardium. Mast cells may have an important role in scar formation through the secretion of growth factors and fibrogenic substances (such as TGF-β, basic FGF, tryptase and VEGF), that may promote collagen deposition and angiogenesis. Understanding the role of the mast cell in myocardial infarction is important in order to design site-specific pharmacological interventions that could mitigate inflammatory injury, without interfering with myocardial healing.

Human tumor cell growth depends on the ubiquitin/proteasome degradation pathway. This pathway is essential in promotion of tumor cellular proliferation, inhibition of programmed cell death (apoptosis), and development of drug resistance, suggesting that proteasome inhibitors could be developed as potential novel anticancer drugs. This hypothesis has been supported by both experimental and clinical results. Most recently, green tea polyphenols (GTPs) containing an ester bond have been identified as a new class of proteasome inhibitors. A mechanistic model to account for the inhibition of proteasome by GTPs has been proposed, evaluated using in silico docking calculations, and validated by comparison of predicted and actual activities of naturally occurring or synthesized GTP analogs. In this review, by following the development of GTPs, traditional methods of drug discovery will be examined including purification and enzymeinhibitor crystal structures. Furthermore, newer techniques such as computational modeling and docking will be evaluated with regards to integration with more traditional approaches. This review will use polyphenol proteasome inhibitors as an example to critically examine the development cycle of drug discovery from compound design, to organic synthesis, to chemical characterization, and then to biological evaluation.

Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have developed a novel therapeutic approach against primary CNS tumors and secondary CNS malignancy complicating systemic cancer based on the human neuropathogen poliovirus. Susceptibility to poliovirus infection and ensuing rapid cell lysis are mediated by the cellular poliovirus receptor CD155, as well as cell-internal factors involved in control of viral gene expression and genome replication. We observed that CD155, a putative cell adhesion molecule of the immunoglobulin superfamily physiologically expressed in the developing CNS, is ectopically expressed on numerous primary and secondary CNS neoplasms. An association with malignant cells renders CD155 a molecular target for therapeutic intervention with poliovirus. However, any therapeutic application of poliovirus must contend with its inherent neuropathogenic potential. Poliovirus gene expression is driven by the viral internal ribosomal entry site (IRES), which mediates translation initiation in a 5'- end, cap-independent manner. We discovered that IRES function is subject to potent cell type-specific restrictions that can be exploited to selectively drive viral gene expression and propagation in cancerous cells. Polioviruses replicating under control of a heterologous IRES derived from their relative human rhinovirus type 2, displayed rapid growth and cell killing in cancerous cells. However, these recombinants failed to efficiently translate their genome and propagate in cells of neuronal lineage. Consequently, polio-/rhinovirus recombinants are non-pathogenic after intraspinal inoculation into mice transgenic for the poliovirus receptor CD155 and in non-human primates. Oncolytic poliovirus recombinants have shown promise in preclinical investigations against primary tumor explant cultures and in xenograft animal studies and are currently being prepared for phase-I clinical trials against glioblastoma multiforme.

Pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate, have been used for more than half a century in the therapy of the parasitic disease leishmaniasis. Even though antimonials are still the firstline drugs, they exhibit several limitations, including severe side effects, the need for daily parenteral administration and drug resistance. The molecular structure of antimonials, their metabolism and mechanism of action are still being investigated. Some recent studies suggest that pentavalent antimony acts as a prodrug that is converted to active and more toxic trivalent antimony. Other works support the direct involvement of pentavalent antimony. Recent data suggest that the biomolecules, thiols and ribonucleosides, may mediate the actions of these drugs. This review will summarize the progress to date on the chemistry and biochemistry of pentavalent antimony. It will also present the most recent works being done to improve antimonial chemotherapy. These works include the development of simple synthetic methods for pentavalent antimonials, pharmaceutically-acceptable liposome-based formulations, for targeting the Leishmania parasites responsible for visceral leishmaniasis and cyclodextrin-based formulations to promote the oral delivery of antimony.

β-glucans (BG) are polysaccharides contained in the cell wall of fungi but also present in nature as normal constituents of oats, barley and yeast. The recent discovery of the major receptor for BG on antigen-presenting cells, dectin-1, has given a strong impetus to a series of researches on BG immunobiological activities. In particular, BG possess antimicrobial activity by exerting a direct effect on monocytes and neutrophils. At the same time, BG-induced removal of inflammatory cells from infectious foci and suppression of proinflammatory cytokines support the antiinflammatory ability of this molecule. BG have been detected in serum of patients with fungal infections and hepatitis C virus infection by means of the Limulus amebocyte lysate assay. Data suggest the antiinflammatory role of BG in these patients, even if the exact nature of circulating BG is still unknown. Of note, clinical trials in patients with postsurgical infections, sepsis and trauma have been conducted by administration of BG in alternative to corticosteroid and anti-cytokine monoclonal antibody (MoAb) therapy which give rise to more serious side effects. As far as anticancer activity of BG is concerned, evidence has been provided that BG behave as an adjuvant for MoAb therapy against tumors. In fact, in a murine model, it was demonstrated that granulocytes with BG bound to CR3 could kill iC3b coated tumor cells, thus potentiating the tumoricidal activity of MoAbs. Taken together, these studies seem to support a beneficial role of BG in the host, even if the exact mechanisms of action of this molecule on the immune network deserves furter elucidation.