Current Medicinal Chemistry - Volume 18, Issue 26, 2011

Three years ago, halting of the Merck & Co Inc clinical trial (STEP trial) and subsequent discovery that this HIV vaccine candidate MRK Ad5 HIV-1 gag/pol/nef had no positive impact but actually caused harm in some of the participants generated lots of pessimism in the research community. After the initial shock, it became apparent, however that valuable lessons were learned from this negative experience. For one, it became clear that vaccine designed to only elicit T cells responses at systemic sites and including a single HIV gene insert, will not be sufficient to reduce transmission or lower viremia in people. It also became apparent that future use of adenovirus-based vectored vaccines needs to be carefully planned with respect to vector type, gene inserts, route of immunization and risk factors among subject volunteers. The inability to come up with a potentially successful HIV vaccine after more than 26 years of efforts and often in a situation where preclinical data was very promising almost completely halted research in this field. The step back however, also generated many questions and influenced research efforts subsequently refocusing considerable amount of research efforts on reliable correlates of protection to vaccines. Of course, ability to develop successful HIV vaccine is tightly related to the development of reliable and clearly defined immune correlates of HIV control. While a substantial number of immune markers were associated with HIV control in the past, this was rarely accompanied with a clear evidence of cause and effect hampering the assessment as to how useful these could potentially be in designing a vaccine or even in predicting the outcome of an HIV infection. New fields of research have also been opened that look into innate immune responses and the ways innate immune responses influence generating acquired immunity. This led to development of Systems Biology approach that among other things looks into novel correlates of protection for vaccines. Recent results from the world's largest HIV/AIDS vaccine trial of more than 16,000 volunteers in which infection has been prevented in 31% of cases generated new excitement among HIV researchers. The trial was sponsored by the US army and the National Institute of Allergy and Infectious Diseases of NIH. Although the level of protection is very low it offered hope that vaccine can be improved and that protective HIV vaccine is possible. Novel molecules such as toll-like receptor agonists and PD-1 receptor ligands antagonists might prove to be powerful in enhancing immune responses as adjuvants to HIV vaccines. Programmed death-1 (PD-1) is a negative immunoregulatory cell surface receptor molecule whose interaction with its ligands PD-L1 and PD-L2 down modulates T-cell immune responses. PD-1 is up regulated on T cells of HIVinfected individuals and high levels of PD-1 on HIV-infected T cells correlate with viral load and with a state of cellular anergy, or ‘ exhaustion’ that results in decreased cellular proliferation, cytotoxic function and cytokine secretion. Interruption of PD-1 with its ligand PD-L1 rescues HIV-infected cells from this state of anergy or ‘ exhaustion’ and presents promising adjuvant to be used for therapeutic or preventative vaccine.....

Mucosal tissues are major sites of HIV entry and initial infection. Induction of a local mucosal cytotoxic T lymphocyte response is considered an important goal in developing an effective HIV vaccine. In addition, activation and recruitment of memory CD4+ and CD8+ T cells in systemic lymphoid circulation to mucosal effector sites might provide the firewall needed to prevent virus spread. Therefore a vaccine that generates CD4+ and CD8+ responses in both mucosal and systemic tissues might be required for protection against HIV. However, optimal routes and number of vaccinations required for the generation of long lasting CD4+ and CD8+ CTL effector and memory responses are not well understood especially for mucosal T cells. A number of studies looking at protective immune responses against diverse mucosal pathogens have shown that mucosal vaccination is necessary to induce a compartmentalized immune response including maximum levels of mucosal high-avidity CD8+ CTL, antigen specific mucosal antibodies titers (especially sIgA), as well as induction of innate anti-viral factors in mucosa tissue. Immune responses are detectable at mucosal sites after systemic delivery of vaccine, and prime boost regimens can amplify the magnitude of immune responses in mucosal sites and in systemic lymphoid tissues. We believe that the most optimal mucosal and systemic HIV/SIV specific protective immune responses and innate factors might best be achieved by simultaneous mucosal and systemic prime and boost vaccinations. Similar principals of vaccination may be applied for vaccine development against cancer and highly invasive pathogens that lead to chronic infection.

The development of an effective HIV vaccine is still hampered by the lack of clearly defined immune correlates of HIV control. Although a number of immune markers have been associated over last years with relative viral control and slower HIV disease progression, these associations are oftentimes complicated by the causality dilemma that does not allow to directly assign cause or effect to the identified parameters. In addition, many of these immune markers may act in concert or represent surrogate makers for otherwise controlled HIV infection. This review will revisit the current knowledge of host genetic and immune markers and their associations with HIV control, particularly examining the roles of virus-specific T cells and humoral immune responses and testing their role as direct correlates of control.

Programmed death-1 (PD-1) is a negative immunoregulatory cell surface receptor molecule whose interaction with its ligands PD-L1 and PD-L2 downmodulates T-cell immune responses. Originally investigated in the context of self-tolerance, PD-1 has more recently been discovered to be upregulated on T cells of HIV-infected individuals. High levels of PD-1 on HIV-infected T cells are correlated with viral load and with a state of cellular anergy, or ‘ exhaustion’ that results in decreased cellular proliferation, cytotoxic function and cytokine secretion. The finding that interruption of PD-1 with its ligand PD-L1 rescues HIV-infected cells from this state of anergy or ‘ exhaustion’ presents the promise for therapeutic intervention. Understanding the molecular signaling pathway(s) of PD-1 may provide opportunities for therapeutic intervention, that may serve as adjunctive therapies to HIV vaccine development. Evidence to date suggests that PD-1 exerts its regulatory effect by interfering with T cell receptor signaling. While certain molecular signals in the PD-1 pathway have been identified, their precise roles and mechanisms of action remain poorly understood. This article reviews what is currently known about PD-1 signaling in human T cells, and more specifically in T cells of individuals chronically infected with certain viruses such as HIV.

The HIV pandemic continues to be a public health crisis with over 30 million people currently living with the disease and, depending on the estimate, another 2 - 2.8 million infected annually. The disappointing results of the first Phase II study of a highly immunogenic adenovirus-vectored vaccine, named the STEP trial, was a wake up call to both the clinical and preclinical HIV vaccine fields. A vaccine designed only to elicit T cells and including a single HIV gene insert, will not be sufficient to reduce transmission or lower viremia in people. Additionally, future use of adenovirus-based vectored vaccines needs to be carefully planned with respect to vector type, gene inserts, route of immunization and risk factors among subject volunteers. The initial observation of a transient, increased risk of infection in Ad5 seropositive, uncircumcised men who have sex with men (MSM) is still unexplained, and may yet be considered simply a random event. The vaccine field has not given up on adenoviruses and there is continued interest in pursuing these highly immunogenic vectors, either in combination approaches with DNA, use of rare serotypes with low seroprevalence, or those derived from simian origin. Finally, evaluation of replicating adenovirus vectors known to be capable of inducing potent cellular, humoral, and mucosal immunity will be vital to meeting our future goal of an effective HIV vaccine.

HIV remains one of the most important deadly infections today, due to the lack of a preventive vaccine and limited access to medical care in developing countries. In developed countries antiretroviral therapy is available but the regime is unable to eliminate the virus, implying that life-long therapy is necessary. Dendritic cells (DCs) are important mediators of cellular and humoral immune responses and hence offer a promising therapeutic vaccination strategy to attenuate disease progression. The current knowledge in DC subsets and their functional plasticity are prominent determinants in harnessing the full immunostimulatory potential of dendritic cells. Type of antigen, immunogen delivery method, optimal interaction of antigenic peptide and T cells, and avoidance of tolerogenic responses are some of the elements that need to be considered to develop an efficient immunotherapy. Novel strategies that modulate DC functions that eventually trigger a robust cellular response against a broad T cell repetoire are needed. This review focuses on current DC-based vaccine strategies for optimal induction of immune responses.

The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

Aberrant activation of the signal transducer and activator of transcription (STAT) 3 occurs in many human tumors. Constitutive STAT3 activity induces specific target genes that stimulate cell proliferation, prevent apoptosis, promote angiogenesis and facilitate tumor immune evasion. Thus, STAT3 is an attractive molecular target for the development of novel cancer therapeutics. Targeting and disruption of oncogenic STAT3 signaling may theoretically be accomplished through various approaches, involving direct and indirect strategies. Small molecular weight compounds have been used for this purpose. This review is intended to be full coverage of the small molecular inhibitors to develop direct STAT3 as a target for cancer therapy and will provide a discussion on the inhibitory modalities developed to date. At present, we retrieved related small molecular inhibitors experimental research papers about STAT3 as a cancer therapy target, the rationale to pursue the protein for the discovery and development of novel anticancer strategies and agents.

Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R2 cv of 0.54, R2 ncv of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R2 pred value of 0.64. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity.

Bile acids (BAs) are a family of steroidal molecules derived from cholesterol and biosynthesised in the pericentral hepatocytes of the liver. Structurally they may be regarded as consisting of two components, a rigid steroid nucleus and a short aliphatic side chain terminating in an alcohol or carboxyl group. Traditionally BAs are known for their ability to act as solubilising agents in the gut, aiding in the absorption of dietary lipids through the formation of mixed micelles. However the identification of BAs as ligands of the farnesoid X receptor (FXR) has lead to the realisation that these molecules have a wider range of biological effects. BAs regulate lipid and glucose homeostasis through activation of the FXR and the G-protein coupled receptor, TGR5. They can activate apoptotic, inflammatory and carcinogenic signalling pathways. BAs have also been shown to have anti-inflammatory effects. Interestingly, BAs are not restricted to the hepatic-intestinal system. Plasma BAs regulate BA synthesis and metabolism. BAs have recently been identified in cerebrospinal fluid. The BA, ursodeoxycholic acid has a potential role as a neuroprotectant in Huntington's disease and its taurine conjugate exhibits neuro-protective effects in vitro that may be relevant to Alzheimer's disease. This renaissance in BA biology has lead to the development of numerous medicinal chemistry programmes with different therapeutic targets, using BAs as lead structures. BA derivatives with increased efficacy and potency for FXR and TGR5 hold significant promise for the treatment of metabolic disorders. The peculiar effects of BAs on cell viability have been exploited for the design of selective cytocidal agents for treatment of various cancers. BA derivatives have also been screened with much success for anti-microbial and antifungal properties. Other targets include carbonic anhydrase for treatment of glaucoma and the glucocorticoid receptor for antiinflammatory effects. In this review interesting recent developments in the medicinal chemistry of these eclectic substances will be discussed.

Coenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology.

As the concepts of pharmaconutrition are receiving increasing attention, it seems essential to clearly assess the effects of specific dietary compounds in specific groups of patients or clinical conditions. We are herein interested in better defining the differential anti-neoplastic effects of the two major n-3 long chain polyunsaturated fatty acids present in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The efficiency of these fatty acids represents a subject of intense interest and debate, and whereas plenty of preclinical studies have strongly demonstrated their preventive and therapeutic effect in different kinds of cancers, the results of the epidemiologic studies are still controversial, and only a few trials have been performed. It has been reported that EPA and DHA may act either through the same or different mechanisms, thus suggesting that a differential efficacy could exist. At present, however, this point has not been clarified, although its better comprehension would allow a more proper and effective use of these fatty acids in the human interventional studies. In an attempt to elucidate this aspect we have herein analyzed the data obtained in the studies which have directly compared the antitumor effects of separate treatments with EPA or DHA. Most of the in vitro data indicate DHA as the more powerful antineoplastic agent. However, an equivalent efficiency of EPA and DHA is suggested by the few in vivo studies. Possible reasons for this discrepancy are discussed and pathways of cell growth that could be differentially influenced by EPA and DHA are described.

This review is the first attempt at systematization and analysis of the literature data (covering the last decade) on the chemical structures and specific activities of cholesterol-regulating agents. Six of thirty currently known biological targets for treating hyperlipidemia were selected and considered. All of the chemical structures under study are divided into two classes with different mechanisms of their activity: cholesterol biosynthesis blockers (HMG-CoA reductase and squalene 2,3-oxide-lanosterol cyclase inhibitors) and regulators of cholesterol transformations in the organism (PPARα and PPARα/γ agonists, inhibitors of intestinal absorption of cholesterol, cholesteryl ester transfer protein (CETP) inhibitors, and regulators of low-density-lipoprotein receptor (LDLR) expression).