Current Pharmaceutical Design - Volume 11, Issue 24, 2005

One of the major challenges raised by HIV chemotherapy is the insurgence of viral resistance to drugs. Resistance to antiviral therapy has been observed for each of the different classes of anti-viral drugs: nucleoside reversetranscriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. The crucial question for AIDS drug research community is: Should we continue the search of new anti-HIV drugs which can overcome HIV resistance insurgence or should we consider resistance to anti-HIV drugs as a futile challenge? This review, focussed specifically on HIV antiprotease drugs, highlights the different strategies which have been developed to design new anti-protease drugs which could overcome HIV resistance, and also reviews the different classes of compounds (peptidomimetic or non-peptidomimetic) actually under investigation in order to face the problem of HIV resistance to drug.

Despite the availability of several classes of drugs against acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type 1(HIV-1), this deadly disease showing very little sign of containment, especially in Sub-Saharan Africa and South-East Asia. More than 20 million people died since the first diagnosis of AIDS more than twenty years ago and almost 40 million people are currently living with HIV/AIDS. Structure-based drug design effort was immensely successful in identifying several drugs that are currently available for the treatment of HIV- 1. Many applications have been reported on the use of quantitative structure-activity relationship (QSAR) studies to understand the drug-receptor interactions and help in the design of more effective analogs. Extensive application was also reported on the application of 3D-QSAR techniques, such as, Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Analysis (CoMSIA), pharmacophore generation using Catalyst/HypoGen, free-energy binding analysis, GRID/GOLPE, HINT-based techniques, etc. in anti-HIV-1 drug discovery programs in academia and industry. We have attempted to put together a comprehensive overview on the 3D-QSAR applications in anti-HIV-1 drug design reported in the literature during the last decade.

This review discusses the recent development of multivalent antibiotics as potential therapeutic agents against infections caused by antimicrobial drug resistant microbes. The discussion focuses on vancomycin because of its important clinical relevance and well-elucidated molecular mechanism of antimicrobial drug resistance. The first section recounts the increased occurrence of vancomycin resistance in the world; the second section briefly discusses the mechanistic study of vancomycin resistance; the third section presents the currently established design principles of multivalent vancomycins; the fourth section examines the structural-activity relationships of multivalent vancomycins; the fifth section describes relevant studies on multivalent antibiotics; and the last section summarizes advantages and limitations of multivalent antibiotics.

Leishmaniasis is the most important emerging and uncontrolled infectious disease and the second cause of death among parasitic diseases, after Malaria. One of the main problems concerning the control of infectious diseases is the increased resistance to usual drugs. Overexpression of P-glycoprotein (Pgp)-like transporters represents a very efficient mechanism to reduce the intracellular accumulation of drugs in cancer cells and parasitic protozoans, thus conferring a multidrug resistance (MDR) phenotype. Pgps are active pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. The inhibition of the activity of these proteins represents an interesting way to control drug resistance both in cancer and in infectious diseases. Most conventional mammalian Pgp-MDR modulators are ineffective in the modulation of Pgp activity in the protozoan parasite Leishmania. Consequently, there is a necessity to find effective modulators of Pgp-MDR for protozoan parasites. In this review we describe a rational strategy developed to find specific Pgp-MDR modulators in Leishmania, using natural and semisynthetic dihydro-β-agarofuran sesquiterpenes from Celastraceae plants. A series of these compounds have been tested on a MDR Leishmania tropica line overexpressing a Pgp transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. Almost all of these natural compounds showed potent reversal activity with different degrees of selectivity and a significant low toxicity. The three-dimensional quantitative structure-activity relationship using the comparative molecular similarity indices analysis (CoMSIA), was employed to characterize the requirements of these sesquiterpenes as modulators at Pgp-like transporter in Leishmania.

Severe sepsis leading to shock is the principal cause of death in intensive care units. It is a systemic inflammatory response caused by excessive secretion of pro-inflammatory mediators, such as tumor necrosis factoralpha (TNFα) and reactive oxygen species (ROS), mainly induced by endotoxin (a major component of the Gramnegative bacterial outer membrane). Immune cells use ROS in order to support their functions and need adequate levels of antioxidant defenses to avoid harmful effects of an excessive ROS production. In addition, nitric oxide (NO) is thought to play a key role in the pathogenesis of sepsis and in the development of multiple organ failure. This article discusses the toxic effects of endotoxin, paying particular attention to cardiovascular damage. It continues by analysing the mechanism by which endotoxin is recognized by specific cells of the immune system, and the pathway leading to nuclear factor-kB (NF-kB) activation and pro-inflammatory gene transcription. 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, their potential clinical use and the effects on the redox state of the immune cells is discussed.

Apicomplexa are unicellular, obligate intracellular parasites of great medical importance. They include human pathogens like Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease (toxoplasmosis). They alone affect several hundred million people worldwide so that new drugs, especially for plasmodial infections, are urgently needed. This review will focus on a recently emerged, potential drug target, a plant-type redox system consisting of ferredoxin- NADP+ reductase (FNR) and its redox partner, ferredoxin (Fd). Both reside in an unique organelle of these parasites, named apicoplast, which is of algal origin. The apicoplast has been shown to be required for pathogen survival. In addition to other pathways already identified in this compartment, the FNR/Fd redox system represents a promising drug target because homologous proteins are not present in host organisms. Furthermore, a wealth of structural information exists on the closely related plant proteins, which can be exploited for structure-function studies of the apicomplexan protein pair. T. gondii and P. falciparum FNRs have been cloned, and the T. gondii enzyme was shown to be a flavoprotein active as a NADPH-dependent oxidoreductase. Both phylogenetic and biochemical analyses indicate that T. gondii FNR is similar in function to the isoform present in non-photosynthetic plastids whereby electron flow is from NADPH to oxidized Fd. The resulting reduced Fd is then presumably used as a reductant for various target enzymes whose nature is just starting to emerge. Among the likely candidates is the iron-sulfur cluster biosynthesis pathway, which is also located in the apicoplast and dependent on reducing power. Furthermore, lipoic acid synthase and enzymes of the isoprenoid biosynthetic pathway may be other conceivable targets. Since all these metabolic steps are vital for the parasite, blocking electron flow from FNR to Fd by inhibition of either FNR activity or its molecular interaction with Fd should also interfere with these pathways, ultimately killing the parasite. Although the three-dimensional structure of FNR from T. gondii is not yet known, experimental and computational evidence shows that apicomplexan and plant enzymes are very similar in structure. Furthermore, single amino acid changes can have profound effects on the enzyme activity and affinity for Fd. This knowledge may be exploited for the design of inhibitors of protein-protein interaction. On the other hand, specifically tailored NAD(P) analogues or mimetics based on previously described substances might be useful lead compounds for apicomplexan FNR inhibitors.

Postoperative nausea and vomiting (PONV) are distressing and frequent adverse events of anesthesia and surgery, with a relatively high incidence after laparoscopic cholecystectomy. Numerous antiemetics have been studied for the prevention and treatment of PONV in patients scheduled for laparoscopic cholecystectomy. Traditional antiemetics, including anticholinergics (e.g., scopolamine), antihistamines (e.g., dimenhydrinate), phenothiazines (e.g., promethazine), butyrophenones (e.g., droperidol), and benzamide (e.g., metoclopramide), are used for the control of PONV. The available nontraditional antiemetics for the prophylaxis against PONV are dexamethasone and propofol. Serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, and ramosetron), compared with traditional antiemetics, are highly efficacious for PONV. The prophylactic ondansetron, granisetron, tropisetron, and dolasetron in antiemetic efficacy are comparable. Ramosetron is effective for the long-term prevention of PONV. None of the available antiemetics is entirely effective, perhaps because most of them act through the blockade on one type of receptor. There is a possibility that combined antiemetics with different sites of activity would be more effective than one drug alone for the prophylaxis against PONV. Combination antiemetic therapy is often effective for the prevention of PONV following laparoscopic cholecystectomy. The efficacy of a combination of serotonin receptor antagonists (ondansetron and granisetron) and droperidol is superior to monotherapy with a serotonin receptor antagonist or droperidol. Similarly, adding dexamethasone to ondansetron or granisetron improves antiemetic efficacy in PONV. Knowledge regarding antiemetics is necessary to completely prevent and treatment of PONV in patients scheduled for laparoscopic cholecystectomy.

Many known pathological conditions lead to decreases in oxygen supply to various cells. When secondary cellular hypoxia becomes severe, it causes additional cellular damage, aggravating the primary disorder and leading to cell death. Therefore, remediation of secondary hypoxic damage should significantly increase the efficacy of the treatment of primary disease and prevent extensive cellular damage. Analysis of the literature and our experimental data show that the main mechanisms of secondary hypoxic cellular damage include lactate acidosis (lactic acidosis), the boost in free radical processes and the activation of apoptosis and necrosis. These factors result in damage to cellular membranes which in turn further limits oxygen supply leading to augmented hypoxic cellular damage. Therefore, to effectively break this vicious cycle of cellular hypoxia, antihypoxic therapy should simultaneously: (1) mitigate existing cellular hypoxic damage; (2) increase cellular ability to utilize available oxygen; (3) amplify the power of cellular antioxidant defense and (4) prevent hypoxic activation of apoptosis and necrosis. It is clear that such complex task cannot be fulfilled by a single pharmacological agent. Therefore, a complex multi component antihypoxic drug delivery system should be designed to address all the four desiderata indicated above. This review will examine existing pharmaceutical antihypoxic preparations and evaluate the new methods for the pharmacological remediation of cellular hypoxic damage and propose future directions for the design of the needed drug delivery systems.