Combination therapy, comprising at least three anti-human immunodeficiency virus (anti-HIV) drugs, has become the standard treatment of AIDS. Since 1996, highly active antiretroviral therapy (HAART) was designed to rapidly control HIV replication. It has had a significant impact on patient health and progression of AIDS in developed countries but its success has not been complete. HAART strategy still suffers from issues of patient compliance, cost, deleterious side effects and emerging drug resistance. Therefore it is logical to look for agents that inhibit different viral targets. In addition to the fusion, reverse transcription and protein formation processes, the HIV replicative cycle offers various other events that can be considered as potential targets for chemotherapeutic intervention. Amongst them integration is a key step and integrase (IN), one of the three viral enzymes, has been rapidly identified as a rational target for many years. To date, four molecules have entered in clinical trials. The present article reviews the increasing number of patents on small molecule HIV-1 integrase inhibitors in the 1998-2005 period, from the pioneer ones (discovery of selective strand transfer inhibitors) to the last patents including the actual molecules under clinical trials.
Antioxidants are essential, and are involved in several important biological processes such as immunity, protection against tissue damage, reproduction, growth and development. Antioxidants preserve adequate function of cells against homeostatic disturbances such as those caused by septic shock, aging and, in general, processes involving oxidative stress. Each year, many scientific articles are published describing the pharmacological and biological properties of antioxidants. This review article compiles recent findings on these properties, focusing mainly on the anti-inflammatory properties of antioxidants in different pathological areas, such as cardiovascular damage and sepsis. In relation to this process, this review focuses on the involvement of reactive oxygen and nitrogen species. Finally, the protective role of antioxidants against homeostatic disturbances such as those caused by endotoxin toxicity and cardiovascular damage, their potential clinical use, and the effects on the redox state of immune cells are discussed.
Tuberculosis (TB) is an important public health problem worldwilde due to AIDS epidemic, the advent of multidrug resistant strains (MDR) and the lack of new drugs in the market. TB is responsible for almost 3 millions deaths each year. According to WHO (World Health Organization), which declared tuberculosis a global health emergency in 1993, tuberculosis, without a coordinated control effort, will infect an estimated 1 billion people by 2020, killing 70 million. In spite of this problem, there is a lack of development of new TB drugs. For example, it has been nearly 35 years since the introduction of a new class of compounds for the treatment of TB. Thus, there is an urgent need for new drugs to fight against this disease. Considering that, this review aims promising drug candidates that are in development against TB.
Many flaviviruses, including yellow fever virus, dengue virus, Japanese encephalitis virus, tick-borne encephalitis virus, and West Nile virus, are globally important human pathogens. Despite an emergence and resurgence of flavivirus-mediated disease, specific therapies are not yet available; however, significant progress has been made toward the prevention and treatment of flavivirus infections. In this article we review recent advances made in the areas of (i) flavivirus vaccine development, and (ii) antiflavivirus drug discovery reported in literature and patents, and highlight strategies used in these investigations.
The complement activation product, C5a, is a potent inflammatory peptide with a broad spectrum of biological functions. Plasma levels of C5a are increased in sepsis, accompanied by increased content of C5a receptor (C5aR) in various organs. In the mouse and rat models of sepsis (cecal ligation and puncture, CLP), C5a blockade by anti-C5a antibody, anti-C5aR antibody or use of a C5aR antagonist (C5aRa) significantly improved survival in CLP animals. C5a blockade in sepsis attenuated the systemic inflammatory response syndrome (SIRS) by reducing plasma levels of IL-6 and decreasing bacteria counts in blood and organs. Anti-C5a treatment in CLP rodents markedly attenuated sepsis-induced defects in the coagulation/fibrinolytic system, while liver and kidney functions were remarkably preserved in contrast to CLP animals not receiving anti-C5a in which multi-organ failure occurs. In CLP rats treated with anti-C5a, thymus atrophy was diminished and thymocyte apoptosis was inhibited. Defective neutrophil functions (chemotaxis, phagocytosis, respiratory burst) caused by sepsis were significantly improved in CLP rats treated with anti-C5a. These data suggest during CLP-induced sepsis C5a has very harmful consequences and that its blockade might be a promising therapeutic strategy for the treatment of humans with sepsis. This review will summarize the beneficial effects of anti-C5a treatment in the rodent model of sepsis and will introduce the most recent patents on this line of research.
The main strategies nowadays to fight AIDS rely on chemical therapy to inhibit the reverse transcriptase or protease of HIV. However, a synthetic 36 amino-acids peptide that blocks the entry of the virus in the target cells (enfuvirtide) has recently reached approval for clinical application. This molecule may probably be just the leader of a new generation of drugs that is about to emerge to interrupt the first step in the HIV life cycle, i.e. preventing the virus from actually entering cells. This paper reviews the enfuvirtide path from clinical trials to the attempts to detail its molecular-level mode of action. It is commonly accepted that this peptide would block the fusion between viral and cell plasma membrane through binding to the N-terminal heptad repeat (NHR) region of the viral protein gp41. However, there has been growing evidence that this model of action may be unrealistic, the action of enfuvirtide being more complex and diverse than initially thought. Membrane-assisted local concentration increase and interference with gp120/co-receptor docking may also contribute for the inhibitory action of the peptide. Selected HIV-entry inhibitors on clinical trials are presented to characterize the future drugs in the market in this class.
Since the 1950s there has been an increase in the incidence of invasive fungal disease. The first successful systemically administered antifungal drug, amphotericin B, was introduced in the 1950s and, until very recently, was considered the best therapeutic drug for severe mycoses. The development of new antifungals to treat systemic disease has been slow compared to that of antibacterial compounds, with the introduction of only a single new class of drugs over the past 20 years. This review discusses the antifungal drugs that are clinically in use and summarizes interesting new applications and patents from the US Patent and Trademark Office.
Five drugs are approved for the treatment of chronic hepatitis B: conventional interferon (IFN) alfa, lamivudine, adefovir dipivoxil, pegylated interferon (peginterferon) alfa-2a and entecavir. Conventional IFN monotherapy has a narrow range of efficacy, should be administered subcutaneously and is commonly associated with adverse effects. Lamivudine is cheaper and well tolerated, but the virological response may not be durable and prolonged lamivudine treatment is commonly associated with the emergence of drug-resistant mutants. Adefovir dipivoxil is potent but with nephrotoxicity at higher doses. Entecavir is active against both lamivudine- and adefovir dipivoxil-naive and -resistant HBV, however, its long-term efficacy remains to be evaluated. Peginterferon alfa-2a has recently been shown to be superior to conventional IFN and lamivudine in the treatment of both HBeAg-positive and -negative chronic hepatitis B. By using peginterferon alfa-2a monotherapy, the overall virological and serological responses are around 30%-44%. However, peginterferon alfa-2a in combination with lamivudine does not improve the results at the end of follow-up. Adverse effects are usually tolerable and comparable with conventional IFN. Similar efficacy of peginterferon alfa-2b has also been demonstrated in HBeAg-positive chronic hepatitis B. These observations suggest an important and even a primary role of peginterferon alfa in the treatment of chronic HBV infection.
Tuberculosis is one of the most devastating bacterial diseases, with increasing rates of morbidity and mortality, despite the presence of effective chemotherapy and Bacillus-Calmette-Guerin (BCG) vaccine. The success of Mycobacterium tuberculosis lies in its ability to spread by aerosol droplets, evade the host immune system and to persist in pulmonary granulomas. The advancement in the field of molecular and cellular microbiology and the availability of transcriptome and proteome data of M. tuberculosis have aided in understanding the pathogenesis of this organism for developing more effective drugs. The current strategy of drug design is to identify gene products, which are essential for survival and virulence. To date, several gene products of mycobacteria, ranging from proteins involved in cell wall synthesis to energy generation and from entry into host to persistence, have been shown to be essential for the survival or virulence of M. tuberculosis. These proteins and their associated pathways are considered as promising drug targets against M. tuberculosis and several of these have been patent protected. Herein, we enlist drug targets against M. tuberculosis for which patents have been filed and issued during the last ten years. The significance of these drug targets in the development of drug is also discussed. This review presents a comprehensive account of the pivotal information for drug discovery and drug design to all researchers involved in tuberculosis research.
Treatments for HIV-1 include drugs which act to inhibit specific steps in the virus life cycle such as reverse transcription and viral maturation. In 1995 breakthroughs were made in our understanding of the entry of HIV-1 into cells. HIV-1 was shown to use, in addition to the CD4 receptor, chemokine co-receptors, primarily CCR5 and CXCR4, for entry into CD4+ T cells and macrophages. These discoveries have provided another target for the treatment of HIV-1 infection. Drugs developed to block HIV-1 entry include CD4 receptor inhibitors, chemokine receptor inhibitors and inhibitors of attachment and membrane fusion. These drugs may add a further treatment for HIV-1 infection along with protease inhibitors and reverse transcription inhibitors. Several of the entry inhibitors are currently being used in clinical trials and demonstrate efficacy in vivo. In this review, the entry blocking drugs that have recently been patented, their mode of action in inhibiting HIV-1 and their efficacy in clinical trials will be discussed.
Quinones are important naturally occurring pigments widely distributed in nature and are well known to demonstrate various physiological activities as antimicrobial and anticancer compounds. This review will focus on the preparation, therapeutic application, and administration of several benzoquinones, naphthoquinones, and anthraquinones having anti-infective, e.g. antiviral and antibacterial activities, in recent patents.