Current Pharmaceutical Design - Volume 9, Issue 11, 2003

Giardiasis is a protozoal disease infecting 200 million people throughout the world. Giardiasis is widespread primarily in developing countries. Infections are correlated with poor hygienic conditions, poor water quality control, and overcrowding. There are very few therapeutics currently available, and drug development to treat giardiasis is hampered mainly by socioeconomic obstacles. This article presents the history of antigiardial chemotherapy and current state of therapeutic availability along with the future prospectus of development of antigiardial agents. In addition to accumulated knowledge about the previous and current antigiardial drugs, advanced technologies including computer-aided drug design and combinatorial synthetic chemistry, as well as high throughput screening techniques, accelerate understanding of the disease and further research toward a suitable antigiardial agent.

This review summarizes some of the published attempts to incorporate protein and NMR structures in the design of new antibiotics that specifically target Cell Wall biosynthesis. Most of the steps involved in peptidglycan synthesis have been investigated as potential strategies against cell wall inhibition. Structural information has been most useful in the design of molecules in the Mur enzyme pathway, penicillin binding proteins and lactamases, as well as proteins that are part of the final steps of transglycosylation - in particular, d-Ala-d-Ala ligase. Several unique issues exist in the design of effective antibacterials, such as the significant differences in protein structure between organisms, such as the case of MurB in which a large amino acid loop that occupies the active site of the E. Coli is gone in the Staph aureus enzyme. Additionally, bacterial resistance is an important issue, and in some cases, structural information can be used to understand the source of this resistance. For example, mutations within the d-Ala-d-Ala ligases lead to the inability of Vancomycin antibiotics to bind.

During its development in the host red cell, the human malarial parasite causes profound alteration in the permeability of the host cell membrane. These membrane transport systems(s) play a role in the development of the intra-erythrocytic parasite in its need to take up solutes and nutrients from the extracellular medium and the disposal of metabolic wastes. Importantly, the properties of these parasite induced transport systems are significantly different from those in normal human cells. Hence, such systems are of considerable interest for their potential use in anti-malarial chemotherapy, both by (i) inhibiting the transport and hence depriving the parasite of nutrients essential for its development, or (ii) by designing cytotoxic drugs which selectively enter the parasite through these induced transporter routes and hence cannot enter normal mammalian cells. Since our discovery that optical isomers of nucleosides (such as Ladenosine or L- thymidine) were selectively transported into malaria infected cells through the induced transporter, L-nucleoside drug “carriers” were actively synthesized as potentially new therapeutic agents. The compounds are dinucleoside phosphate dimers, where each ”carrier“ (a L-nucleoside) has been conjugated to known anti-malarial agents, such as 5'-fluro-uridine through the 3' and 5'-OH and a phosphate group. A very large series of these drugs have been synthesized with varying conjugations. The dimers are extremely toxic against malaria and experimental evidence has confirmed that they are incapable of entering normal mammalian cells. This review discusses their mechanism of action and potential as new anti-malarial chemotherapy as well as the role played by the membrane transport system of malaria infected cells as a target for malaria chemotherapy.

In the last several decades the plants, animals and microbes from the marine environment have revealed a portion of what is clearly a tremendous resource for structurally diverse and bioactive secondary metabolites. Many of these extraordinarily sophisticated and bioactive natural products can be isolated in significant quantities without great difficulty. As a result these readily available bioactive natural products provide valuable starting materials for the rational generation of libraries of compounds prepared through semisynthesis and biocatalysis. A review of our work using marine natural products to generate rationa-lly designed compound libraries and their biological activity against infectious diseases, cancer and neurological targets is presented. The marine natural products utilized to date as starting materials consist of compounds from a variety of structural classes and include: aureol, puupehenone, sarcophine, palinurin, and the manzamine alkaloids. The possibility to generate diverse bioactive products beginning with a marine natural product scaffold is a direct result of improvements made in the technologies to harvest samples from the ocean, purify and characterize complex natural products quickly and complete chemical reactions and biotransformations in parallel. As a result the vast resources of the ocean can now be utilized routinely to design and produce countless products to be evaluated as part of drug discovery and development programs.

Drug discovery is an expensive, slow and high risk enterprise. Only one in ten of the agents that enter clinical development is successful, with an average cost of $500-800 million and a typical time-scale of 10-15 years from preclincal discovery research to regulatory approval. On the other hand, many new targets are emerging from genome sequencing and the improved understanding of molecular pathology. Also, new technologies are increasing the speed and improving the efficiency of drug discovery. These new advances should facilitate progress towards the development of personalised therapies that are targeted to the genetics and molecular pathology of individual patients. The availability of pharmacokinetic (PK) and pharmacodynamic (PD) endpoints is absolutely critical to modern drug development. They allow us to understand how much of the drug gets there (into the body and ideally to the target cells) and what it does (with respect to modulation of the molecular target and the cognate biochemical pathways and downstream biological effects). PK and PD endpoints allow us to construct a pharmacological audit trail, so that all of the successive stages from drug administration through to biological effects and clinical outcome can be monitored and interpreted. This in turn provides a rational basis for decision making, e.g. stop / go, during development. An understanding of PK / PD relationships also gives us s basis for selecting the optimal drug dose and schedule. Better, less invasive methods are required. Developments in molecular / functional imaging show promise and current examples are provided.

Nuclear Medicine involves studying the time course of radioactive tracers and the physiological response of the body in vivo using external imaging devices. These devices are quantitative and can be used to assay tracer concentrations. This chapter briefly discusses the historical milieu, current state-of-the-art in terms of both single photon and positron tomography (SPECT and PET), and shows a semi-quantitative example of monitoring response to anti-cancer treatment with readily available instrumentation (a gamma camera) and radiopharmaceutical ([18F]-FDG). Nuclear Medicine is being increasingly utilised in drug discovery and development, and its role looks set to increase even further in the future.

Positron emission tomography (PET) provides the oncologist with information on tumour diagnosis, and treatment response monitoring. Mathematical modelling of tissue data, and online plasma radioactive metabolite profiling, enables important tissue kinetic parameters relating to the uptake, distribution and washout as well as arterial input function to be derived. The resultant kinetic data allow for not only diagnosis but also the assessment of therapeutic response endpoints. These endpoints can be used to measure specific therapeutic effects. This novel application of PET can provide information that is often difficult to measure in the intact animal or patient. The pharmacokinetics of radiolabelled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), temozolomide and 5-fluorouracil (5-FU) are described.

Positron Emission Tomography (PET) offers an exciting opportunity to monitor key pathways involved in malignant transformation due to the ability to radiolabel and image the behaviour of biological probes. In this review, we will describe how PET can use various radiolabelled compounds to monitor various targets including ligand-receptor interactions using 16α-[18F]fluoro-17β-oestradiol (FES) pathways involved in metabolism with [18F]fluorodeoxy-glucose ([18F]FDG), 11C-methyl-choline for signal transduction, cell cycle and proliferation with 2-[11C]thymidine, cell death using [124I]annexin V, [11C]colchicine for drug resistance and angiogenesis using [124I]anti-VEGF.