Compound-induced host cell responses and effects onwhole virus

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Local needs

In the South African context, identifying novel therapy specific to the subtype C strain is very important because this strain (which is prevalent in this part of the world, Nkolola and Essex, 2006, Wouter et al., 1997) has not been as widely studied as the subtype B virus found in developed countries. Currently administered medications were synthesised using the subtype B viral strain and even though these drugs are active against non B strains e.g. C, effectiveness is less with a resultant increase in the incidence of mutations (Kantor and Katzenstein, 2004). In addition, the cost of current medication cannot be met by the poor (Ford et al., 2007) making the identification of local, more effective and potentially cheaper therapies a necessary endeavour. This was one of the reasons that led to the creation of the Project AuTEK Biomed Consortium which is affiliated with two mining companies in South Africa (Mintek and Harmony Gold) and South African universities. The idea here was that the natural availability of pure gold deposits in South Africa could be exploited for possible health benefits by using gold in synthesising potential drugs.
Taken together, all the shortcomings in managing HIV and AIDS, coupled with the fact that no available vaccine or cure has been discovered necessitates the continuous search and identification of novel treatment options that can be used to supplement or replace currently available drugs. In the next section, an introduction to the drug development process will be provided followed by a discussion on the use of metals in medicine with specific emphasis on gold-based compounds.

DRUG DEVELOPMENT

Drug development and discovery can be a very tough and long process both scientifically and financially for the pharmaceutical industry and it can typically take up to a decade for a drug to go through the different phases of drug discovery (Fishman and Porter, 2005), which are shown in Figure 2.18. These phases include the lead or target discovery phase during which important molecular targets are identified. This phase can typically take a year to several years (Fishman and Porter 2005). This is followed by the preclinical phase where toxicity, efficacy and dose response is determined using both in silico and in vitro techniques and involves technologies that range from traditional high throughput screening (HTS) to affinity selection of large libraries, fragment-based techniques and computer-aided design (Keseru and Makara, 2006). In phase I/II, biomarkers and response to treatment are monitored together with adverse responses and efficacy in humans. Successful candidates which go through these preliminary phases are finally entered into phase III/IV, a phase which involves the prediction of adverse responses and efficacy monitoring at a larger scale and finally approval and clinical application of the successful drug candidate. In the course of the discovery process, drug-like properties which include; absorption, distribution, metabolism, excretion and toxicity (ADMET) are monitored. Compounds that are drug-like are defined as those compounds that have sufficiently acceptable ADMET properties to survive through the completion of human Phase I clinical trials (Lipinski, 2000). Identifying drug-like compounds has become increasingly important after it was observed in the late 1990s that the main causes of late-stage failures in drug development were as a result of poor pharmacokinetics and drug toxicity (Lombardo et al., 2003, van de Waterbeemd and Gifford, 2003). The introduction of ADMET screens in the early phases of drug discovery avoids loss in expenditure by pharmaceutical companies downstream the discovery process when it becomes apparent that the compounds are not drug-like. In the past, focus on determining binding to the active site was a strong priority in discovery for medicinal chemists where HTS and traditional medicinal chemistry techniques were employed (Kerns and Di, 2008). The focus in modern day drug discovery is on structure activity relationships (SAR, Di and Kerns 2003). The latter has been enhanced by the development of virtual (in silico) screening techniques, which have been emerging in the past decade and are now perceived as complementary approaches to experimental HTS (Desai et al., 2006). Coupling experimental HTS and virtual screening with structural biology, promises to enhance the probability of success in the lead identification stage of drug discovery. The combinations of these techniques have not only led to increased output but through SAR or rational drug design studies, medicinal chemists can easily correlate pharmacological and biological properties (Kerns and Di, 2008). The earliest impact of this was the decrease in late failures from 39% in 1998 to 10% in 2000 (Kola and Landis, 2004).

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CHAPTER 1
INTRODUCTION
CHAPTER 2
LITERATURE REVIEW AND BACKGROUND
2.1 HIV AND AIDS
2.2 DRUG DEVELOPMENT
2.3 METALLODRUGS
2.4 HYPOTHESIS AND MAIN RESEARCH QUESTIONS
2.5 SCREENING STRATEGY AND METHODOLOGY
2.6 OTHER RESEARCH OUTCOMES
CHAPTER 3
GOLD COMPOUNDS: STRUCTURE AND DRUG-LIKENESS
SUMMARY
3.1 INTRODUCTION
3.2 COMPOUNDS
3.3 MATERIALS AND METHODS
3.4 RESULTS AND DISCUSSION
3.5 CONCLUSIONS
CHAPTER 4
COMPOUND-INDUCED HOST CELL RESPONSES AND EFFECTS ONWHOLE VIRUS  SUMMARY
TABLE OF CONTENT
4.1 INTRODUCTION
4.2 MATERIALS AND METHODS
4.3 RESULTS AND DISCUSSION
4.4 CONCLUSION
CHAPTER 5
COMPOUND EFFECTS ON VIRAL ENZYMES
SUMMARY
5.1 INTRODUCTION
5.2 MATERIALS AND METHODS
5.3 RESULTS AND DISCUSSION
5.4 CONCLUSION
CHAPTER 6
TABLE OF CONTENT
CONCLUDING DISCUSSION & FUTUREWORK
6.1 COMPOUNDS: STRUCTURE AND DRUG-LIKE PROPERTIES
6.2 EFFECTS OF COMPOUNDS ON HOST CELLS ANDWHOLE VIRUS
6.3 EFFECTS OF COMPOUNDS ON VIRAL ENZYMES
6.4 ANSWERS TO RESEARCH QUESTIONS
6.5 RECOMMENDATIONS
6.6 NOVEL CONTRIBUTIONS
6.7 FUTURE WORK
6.8 CONCLUSION
CHAPTER 7
REFERENCES
CHAPTER 8
APPENDIX
8.1 CHAPTER 2
8.2 CHAPTER 3
8.3 CHAPTER 4
8.4 CHAPTER 5
GLOSSARY 

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