Current Medicinal Chemistry - Volume 13, Issue 20, 2006

Wild-type Wilms' tumor gene WT1 is highly expressed not only in hematopoietic malignancies, including leukemia and myelodysplastic syndromes (MDS), but also in various kinds of solid tumors. Human cytotoxic T lymphocytes (CTLs) which could specifically lyse WT1-expressing tumor cells with HLA class I restriction were generated in vitro. We have also demonstrated that mice immunized with the WT1 peptide or WT1 cDNA rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to normal organs which physiologically expressed WT1 in prophylactic and therapeutic models. Furthermore, we and others detected IgM and IgG WT1 antibodies in the patients with hematopoietic malignancies, indicating that WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing WT1- specific cellular immune responses were elicited in the patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of the findings mentioned above, we performed a phase I clinical trial of WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that WT1 peptide cancer vaccine had efficacy in the clinical setting, because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of TAA-derived cancer vaccine may be enhanced by combination with stronger adjuvants, helper peptide, or conventional treatments such as molecular-target-based drugs.

Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. Over 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase (pol) pol λ can synthesize DNA both in a template dependent (DNA polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. Pol λ might be involved in the nonhomologous end-joining (NHEJ) recombinational repair pathway of DNA double strand breaks (DSBs). Specific inhibitors of these enzymes hold the potential to be developed into a novel class of antitumoral agents. In this review, we will summarize the recent advances in the synthesis and characterization of the first classes of specific inhibitors of mammalian terminal transferases and their potential applications.

Enfuvirtide (Fuzeon®, Roche), is the first member of a novel class of antiretroviral agents, the socalled fusion inhibitors, which act against HIV with a completely novel (extra cellular) mechanism of action, and can therefore be easily added to all anti-HIV association therapies including all other antiretroviral agents belonging to nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, since no interactions of any type are expected with enfuvirtide. Despite the need of a twice-daily parenteral (subcutaneous) delivery due to the polypeptide structure of the drug, and its proportionally short elimination lifetime, two extensive multicentre randomized clinical trials and a huge amount of other clinical and laboratory experiences confirmed the elevated potency and the safety profile of enfuvirtide in appropriate samples of HIV-infected patients (both adults and children), who failed and/or became intolerant to all previously available anti-HIV regimens, and had a very restricted choice of antiviral compounds showing residual activity. As a consequence, enfuvirtide is recommended as an adjunct to an "optimized background" containing at least one or two antiretroviral drugs, which are still active against the isolated viral strain, as assessed by resistance testing. The extremely promising profile of this novel anti-HIV drug and the reduced potential for the development of viral resistance (with no possibility of cross-resistance with the other anti-HIV classes) however warrant further pharmacokinetic, pharmacodynamic, pharmacogenomic, and pharmacoeconomic investigation. Also more extensive and prolonged clinical and quality of life studies are strongly needed to establish the best positioning of enfuvirtide in the current therapeutic guidelines of HIV disease and its future role, besides its current approval for salvage therapy of adult and pediatric HIV-infected patients with limited therapeutic options.

The enzyme protein:geranylgeranyl transferase-1 (PGGT-1 or GGTase-I) catalyzes the geranylgeranylation of cysteine residues near the C-termini of a variety of proteins, including most monomeric GTP binding precursor proteins belonging to the Rho, Rac and Rap subfamilies. These proteins are involved in signaling pathways controlling important processes such as cell differentiation and growth. In the framework of the development of therapeutics against disorders associated with aberrant cell proliferation, the interference with these signal transduction cascades has been a major focus of investigation. For instance inhibitors of PGGT-1 have shown promise in the treatment of cancer, smooth muscle hyperplasia as well as parasitic infections, such as malaria. In this review, structural and mechanistic aspects of the protein:geranylgeranyl transferases are discussed as well as their importance with respect to the terpene metabolism. An extensive summary of reported inhibitors of PGGT-1, classified as natural products, peptide substrate (Ca1a2L box), terpene substrate (geranylgeranyl pyrophosphate) and others, is presented. The few known inhibitors of the other geranylgeranylating enzyme, protein:geranylgeranyl transferase-2 (PGGT-2), are also included.

The arsenal of drugs in the fight against AIDS is rapidly diminishing as the HIV becomes resistant to the available reverse transcriptase and protease inhibitors. After killing millions all over the world, the virus is still on the rampage and hence the pharmaceutical industry is resorting to the development of inhibitors of integrase. This seems to be the last arrow in the quiver of potential drug leads to combat the deadly infection. Several classes of HIV integrase inhibitors have been reported to date; however, none is clinically useful. This review details the existing knowledge of the biological functions of the HIV-1 integrase with the focus on its available inhibitors, their disadvantages, and the current trends in designing novel compounds as antiintegrase.

Cardiovascular disease (CVD) is the leading cause of death among patients with end-stage renal disease (ESRD). Vitamin D deficiency accompanies the loss of kidney function and is extremely common. Treatment with active vitamin D has improved survival rate in dialysis patients. The relationship between vitamin D and CVD has been reported in the literature. Genetic factors have been known to cause both vitamin D deficiency and CVD. Vitamin D receptor is found in the heart muscle. Vitamin D is reported to be involved in the pathogenesis of many cardiovascular problems. Certainly, vitamin D has an important role in modulating CVD.

Despite the fact that they have been used for a century to treat several kinds of diseases, peptides and short proteins are now considered the new generation of biologically active tools. Indeed, recent findings suggest a wide range of novel applications in medicine, biotechnology, and surgery. The efficacy of native peptides has been greatly enhanced by introducing structural modifications in the original sequences, giving rise to the class of peptidomimetics. This review gives an overview of both classical applications and promising new categories of biologically active peptides and analogs. Besides the new entries in well known peptide families, such as antibiotic macrocyclic peptides, integrin inhibitors, as well as immunoactive, anticancer, neuromodulator, opioid, and hormone peptides, a number of novel applications have been recently reported. Outstanding examples include peptide-derived semi-synthetic vaccines, drug delivery systems, radiolabeled peptides, self-assembling peptides, which can serve as biomaterials in tissue engineering for creating cartilage, blood vessels, and other tissues, or as substrates for neurite outgrowth and synapse formation, immobilized peptides, and proteins. Finally, peptide-based biomaterials can find applications in bio-nanotechnology for bio-microchips, peptide nanorods and nanotubes, bio-sensors, bio-electronic devices, and peptide-metal wires.