Current Pharmaceutical Design - Volume 10, Issue 15, 2004

This review focuses on our approach to the study of the effect of a series of phosphoramidate substituted nucleoside analogs on model systems for cancer, HIV and fertility. This approach allowed the development of compound WHI-07, an arylphosphoramidate derivative of zidavudine. This compound is a multifunctional agent showing potent activity in the above mentioned model systems. Our rational drug design provided Read More

Mast cells and basophils are major effector cells in the immunoglobulin E (IgE)-dependent allergic reactions as well as in the innate immunity. They are distributed throughout the body and, upon allergen exposure, are stimulated via the high affinity IgE receptor (FcεRI) to release several pro-inflammatory mediators such as leukotrienes, immunoregulatory cytokines and histamine. FcεRI-mediated signaling is initiated by tyrosi Read More

The spleen tyrosine kinase Syk is an enigmatic protein tyrosine kinase functional in a number of diverse cellular processes. It is best known as a non receptor protein tyrosine kinase involved in signal transduction in cells of hematopoietic origin and plays a crucial role in signaling in most of these cells. It is involved in B and T-cell function, platelet aggregation, mast cell signaling, neutrophils and macrophages. Recently it has been f Read More

The cellular signaling machinery is a complex network of cross-talking proteins that enables dynamic communication between upstream causal factors and downstream effectors. Non-receptor tyrosine kinases, including Src, are the intermediates of signal transfer, controlling pathways as diverse as cell growth, death, differentiation, migration, and genome maintenance. When expressed as viral genes these proteins are p Read More

BTK (Bruton's tyrosine kinase) is a member of the TEC family of tyrosine kinases that plays a central but diverse modulatory role in various cellular processes. The unique role of BTK in a multitude of signaling pathways, its function as a dual regulator of apoptosis and its involvement in a number of developmental processes makes BTK a desirable target for potential anti-cancer, anti-inflammatory and anti-viral agents as well as ot Read More

Here we discuss the therapeutic potential of Janus kinase 3 (JAK3) inhibitors as a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory, anti-allergic, anti-thrombotic and anti-leukemic properties. JAKs are abundantly expressed in primary leukemic cells from children with ALL (acute lymphoblastic leukemia) and are crucial for signals regulating apoptosis. Additional roles for JAK3 in mast cell-m Read More

BMS-378806 is a prototype of a new class of small molecule HIV-1 inhibitors that blocks viral attachment to cells. This compound exhibits potent inhibitory activity against a panel of HIV-1 laboratory and clinical isolates (M- and T-tropic), selective for HIV-1 and inactive against HIV-2, SIV and a panel of other viruses. BMS-378806 exhibits no significant cytotoxicity and displays many attractive pharmacological properties such as l Read More

The use of HAART with double or triple drug combinations has significantly improved the survival of AIDS patients. However, the emergence of virus-drug resistance and both short- and long-term drug-related side effects are among the main reasons for continuing the development of new classes of effective anti-HIV drugs that target the replicative cycle at different sites. In recent years, tremendous progress has been ma Read More

The recent success of the fusion inhibitor T-20 (enfuvirtide) in clinical studies has ushered in a new chapter in the development of anti-HIV-1 therapeutics. T-20 is the first FDA-approved drug that targets the viral transmembrane protein gp41. This protein, along with gp120, promotes viral entry through a coordinated cascade of conformational transitions that lead to the fusion of the HIV-1 and target cell membranes. The i Read More

The gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein plays an important role in HIV-1 entry and severs as an attractive target for development of HIV-1 entry inhibitors, a new class of anti-HIV drugs. Triggered by gp120 binding to CD4 and a coreceptor, gp41 undergoes a conformation shift from a native prefusogenic state to a fusogenic state, in which the N-terminal heptad repeat (NHR Read More

An increasing number of human immunodeficiency virus (HIV)-infected patients have detectable viraemia despite treatment with multiple-drug combinations or have developed resistance to all available classes of antiretroviral therapy. HIV entry has become an important pharmacological target. Enfuvirtide is the first HIV entry inhibitor to be approved for the treatment of drug-experienced patients but several other agents Read More

Inhibiting the HIV-1 entry process offer a new therapeutic target and the hope to potentialize our current treatments against wild-type or drug-resistant viruses. Several inhibitors of CD4, co-receptor CCR5 or CXCR4 and fusion are at various levels of clinical development. How best to use this class of drugs in our therapeutic arsenal remains to be defined. It is likely that these compounds will not be used as monotherapy. There Read More