Mini Reviews in Medicinal Chemistry - Volume 6, Issue 2, 2006

Probing for Antiparasitic Drugs Every person on earth is infected by at least several parasites. The most dangerous parasites are transmitted by vectors and cause the death of millions annually. In order to reduce mortality resulting from such infections there is a need to interrupt the life cycle of the parasites. A parasitic disease will not be eradicated unless efforts to contain it below a "critical mass" succeed. The critical mass may be defined as a combination of a minimum number of infected human, infected reservoir animals (when relevant, e.g. leishmaniasis), and a minimum amount of vectors (e.g. Simulium in river blindness). A failure to control the vectors and insufficient treatment of human patients originates from the increasing resistance of the vectors to insecticides and from parasite drug resistance. In addition, economic considerations are highly responsible for the prevalence of the diseases. In this issue our aim is to consider novel and recent approaches to chemotherapy of vector-born parasitic diseases. Recent advances regarding the biology, physiology and biochemistry of the parasites have led to the recognition of new targets for chemotherapy. These targets must be specific in order to increase the therapeutic value of the drug. Lead optimization may help in designing new drugs such as enzyme inhibitors. For example, cysteine proteases of various parasites could be an important target; in malaria parasites they are involved in hemoglobin degradation and in Leishmania parasites in digestion within lysosomes/endosomes. A second approach to drug discovery is based on the screening of traditional drugs. Some of these compounds were used long before the understanding of their mechanism of action and some are still in use despite their unknown mechanism (e.g. quinine). A third approach aims at improvement of existing drugs by derivatization, which enables better transport to the target cell/organ (e.g. diamidine derivatives against sleeping sickness) or slow release in order to allow for sufficient stable amounts of the drug. Despite the continuous, extensive studies being carried out, the amount of newly approved effective anti-parasitic drugs in the last 5 years, is frustrating and can be counted on the fingers of one hand. A main reason for the limited success of developing new drugs is the lack of understanding of mechanisms of drug action which are additional to the direct anti-parasitic effects. While it is relatively easy to examine drug effects on in vitro cultures of the parasite, the actual activity, efficacy and safety of drugs depend on various factors. These include the direct anti-parasitic effect, and the effect on immune and physiological functions. These considerations could be demonstrated by artemisinin and its derivatives. Artemisinin is a prodrug which is transformed to the active derivative dihydroartemisinin (DHA). It is a common dogma that it is active because it contains a peroxide bridge which interacts with iron to form a reactive free radical. Despite its accumulation in the parasitized erythrocyte its high anti-malarial therapeutic index can not be solely attributed to its radical activity. DHA in vitro kills bacteria, various protozoa (e.g. Leishmania) and animal cells at μM concentrations. However, the ID50 for malaria parasites is lower than 1 nM. This low ID50 has been attributed to DHA's activity against the plasmodial SERCA (Ca-ATPase). There are additional effects which are not anti-parasitic but affect the fate of the malaria infected patient: DHA reduces vascular endothelial growth factor (VEGF) which consequently may affect the pathogenesis of in vivo infection. Moreover, treatment with high concentrations of DHA may suppress both humoral and cellular immune responses. Low concentrations may stimulate T-lymphocyte cell mediated responses. The therapeutic index of a drug would be increased if large amounts could be targeted to the affected host organ and parasite molecule. The outmoded former drug chloroquine was a most valuable drug because it was accumulated in the parasitized erythrocyte and has a specific target which is related to hemoglobin degradation and hemozoin formation. Chloroquine is not in use any more due to plasmodial drug resistance. It took more than 20 years until chloroquine resistance spread throughout all endemic areas. However, sometimes it is possible to predict the probability of induction of drug resistance by exposing the parasites to increasing quantities of the drug and by using molecular markers. J. Clos and K. Choudhury use functional cloning as a means to identify Leishmania genes involved in drug resistance. Resistance to established anti-leishmanial drugs is a mounting problem in high-endemicity regions and in the context of HIV-Leishmania coinfections. The molecular basis for clinical ........

Resistance to anti-leishmanial drugs is a mounting problem in high-endemicity regions of South Asia and, potentially, in the context of HIV-Leishmania coinfections in Southern Europe. The molecular basis for clinical drug resistance is still largely unknown. It is important, however, to identify all relevant drug resistance markers for further drug development and for epidemiological surveys. An elegant and powerful method to identify such drug resistance markers without bias is functional cloning, using cosmid-based genomic DNA libraries. This review discusses the merits and caveats of this approach.

Many similarities exist between cancer cells and parasites. A potentially lucrative starting point for the discovery of novel drugs to combat parasites is to examine available compounds developed against cancer for antiparasitic properties. Here, we review the use of current and promising anticancer agents for treating major human parasitic diseases.

The leishmaniases consist of visceral and cutaneous syndromes present in > 30 endemic regions of the world. Miltefosine (hexadecylephosphocholine) is the first oral agent that is effective and tolerated for both visceral and cutaneous disease in several endemic regions, and represents a major advance in the treatment of these diseases.

The clinical treatment of leishmaniasis is based on a limited number of drugs, which are associated with adverse effects and have already induced resistance. Amphotericin B (AmB), a polyene antibiotic produced by Streptomyces sp, is the only anti-leishmanial drug which has not induced clinical resistance since its discovery in 1956. The limiting factor in the use of AmB is its toxic effects, mainly nephrotoxicity. The maximal dose of AmB for human use is 1.5 mg/kg which sometimes is not sufficient for cure. The mode of action of AmB is associated with its toxicity: it selectively binds to parasite membrane ergosterol but also, to a lesser extent, to human cholesterol. Apart from this mechanism, AmB has immunomodulatory effects, some of them are deleterious. Reduction of the toxic effects by using lipid formulations allows the infusion of higher doses of AmB. Unfortunately, these formulations are relatively expensive and therefore out of reach for patients in need, in the endemic areas. All the existing formulations are given parenterally, which has obvious disadvantages; most important is the need for hospitalization or multiple visits in the clinic. The current efforts to improve AmB are directed at the production of AmB aggregates in liquid solutions, encapsulation with lipid components, and solubilization by binding to soluble polymers. The expected improved treatment resulting from use of the new formulations is based on better pharmacokinetics, reduced toxicity originating from slow release, targeting to the infected organ and an altered pattern of immune responses (related to AmB). Of particular importance are the attempts to produce derivatives for oral treatment, which will decrease costs of hospitalization and improve applicability for children and the elderly population.

Antimalarial drugs are urgently and continuously required. Parasite enzymes involved in antioxidant defence represent interesting target molecules for rational drug development. Here we summarize the currently available data on structural, biochemical, and functional properties of these proteins in an attempt to evaluate and compare their potential as drug targets.

Over 300 million cases of malaria each year cause significant morbidity and mortality. Growing drugresistance among the Plasmodia that cause malaria motivates the development of additional anti-malarial drugs. This review summarizes the current state of knowledge about potential drug targets for malaria. The recently sequenced malaria genome data clarifies parasite metabolic pathways, and more metabolic targets have been identified.

Wolbachia endosymbionts of filariae are targets for the development of new antifilarial chemotherapy. Doxycycline to deplete Wolbachia from the worm has demonstrated the feasibility of this strategy and has provided a new chemotherapeutic tool. Recent research shows that depleting Wolbachia will also lessen pathology, and lessen adverse reactions to traditional antifilarial drugs.

Free radicals may be reaction intermediates in biological systems in more situations than are presently recognized. However, progress in detecting such species by Electron Spin Resonance (ESR) has been relatively slow. ESR is a very sensitive technique for free radical detection and characterization. It can be used to investigate very low concentrations of radicals provided that they are stable enough for their presence to be detected. For unstable radicals special techniques have to be employed. One of these methods is called Spin Trapping. Parasitic diseases in tropical and subtropical areas constitute a major health and economic problem. The range of antiparasitic drugs varies widely in structural complexity and action at the subcellular and molecular levels. However, a number of these drugs are thought to exert their action by generating free radicals. Most of the free radical producing drugs used against parasites are: quinones, naphtoquinones, quinone-imines, aminoquinolines, N-oxides and nitroheterocyclic compounds. This review summarizes some of the more relevant achievements of ESR and Spin Trapping applications in parasitic diseases studies. The use of ESR spectroscopy to obtain relevant information about free radical characterization and the analysis of the mechanisms of action of drugs involved in several parasitic diseases is also presented.

Thyrotropin releasing hormone (TRH: pyroglutamic acid-histidine-prolineamide) regulates the activity of cells in the anterior pituitary and within the central and peripheral nervous systems. TRH, which has been the subject of much research over the past three decades, exerts its effects by acting through class A G-protein coupled receptors. The recent discovery of a second receptor subtype has generated an interest in the discovery of receptor subtype-selective TRH analogs. In this review, we describe advances in the development of TRH analogs and in the understanding of their mechanism of interaction with TRH receptors. We also describe the recent breakthrough in the identification of analogs that bind selectively at TRH-R2.

Most solid tumors are angiogenesis dependent. Anti-angiogenic pharmaceuticals that inhibit the growth of new blood vessels offer considerable promise as anti-cancer agents. With increasing numbers of antiangiogenic drugs in clinical trials, there is an urgent need for detailed characterization of the heterogeneity of tumor vasculature and dissection of the complex network of mechanisms that control tumor angiogenesis. Non-invasive molecular imaging will play a key role in individualized anti-angiogenic therapy based upon molecular features of the new blood vessel growth. Integrin αvβ3, which binds several ligands via an RGD tripeptide sequence, is uniquely expressed in tumor vasculature and aggressive tumor cells, making it a potential target for anti-angiogenic interventions. This review highlights some recent advances in multimodality imaging of tumor integrin expression with emphasis on positron emission tomography (PET).

Oxidative stress plays an important role in the pathogenesis of asthma. Recently several investigators have studied the effects of a variety of antioxidants on asthma. Antioxidants, including L-2- oxothiazolidine-4-carboxylic acid, reduce airway inflammation and hyper-responsiveness of asthma and may be novel therapeutic agents for asthma.

Proteomics is becoming an important research area for studying protein expression patterns induced by different external stimuli. An important aspect of proteomics is to identify and quantify proteins. Many new technologies and techniques have been developed in this field and have been applied to various aspects of drug discovery.