Antiviral Research and Development Against Dengue Virus

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Table of Contents,Part 1 Antivirals 3, A short historical view on antiviral research and therapies 3. Lessons learned from recent viral diseases and pandemies 3. The methods used to discover antivirals 4,Infected cell assays 5. Knowledge based methods 5,The source of anti infectious molecules 6. Why has natural product screening been neglected in antiviral research 8. Challenges associated with natural products in antiviral research 8. What is a validated antiviral target 9,Animal models 9. Patient cohorts and clinical trials 10, Frequent arguments about antiviral therapy feasibility 10.
The introduction of dengue as a druggable disease 11. Diagnostics and what does it tells us for antiviral therapy 11. Current treatment 11,Part 2 Dengue 13,Preamble 13,The Dengue Virus 13. The DENV targets for antiviral research 13,Overview of genome organisation 14. Overview of the DV particle and DV proteins as targets for drugs 14. The structural proteins 14,The Non Structural proteins 15. RNA structures 17,The dengue validated targets 17, The cellular targets for antiviral research against dengue 18. siRNAs as tools and or therapeutic agents 19,Response modifiers 20.
Monoclonal antibodies 21,Mechanical devices 21, Part 3 Academic and academy associated research centers 22. Part 4 The current industrial network of AV discovery 31. Part 5 Mapping the dengue drug design effort and needs 38. Annex 1 References 42,Annex 2 Patents 43,Part 1 Antivirals. A short historical view on antiviral research and therapies. The first significant successes of anti infectious disease treatments originated from the discovery and. use of antibiotics The discovery of many viruses preceded largely the discovery of the first antiviral. molecule which occurred at least 40 years after that of penicillin in 1928 The first documented. description of an antiviral molecule that of 5 iodo 2 desoxyuridine occurred in 1959 It was. discovered active against Herpes ophthalmologic infections and followed by a series of related active. molecules The fight against herpes was the perhaps the earliest and most significant driving force of. antiviral research Herpes was the only significant viral disease for which all technical elements and. systems required to develop an antiviral molecule first became available i e in vitro infected cell. systems animal models chronically infected patients The antiviral drug field came of age in the. next decades with the first antiviral molecule finding its way to the clinic Gertrude B Elion. discovered acyclovir 2 a scientific breakthrough for which she was later awarded the Nobel prize in. 1988 The subsequent emergence of AIDS in 1981 and the following pandemics drastically changed. the field of antiviral research allowing the widening of concepts technical developments rules and. Lessons learned from recent viral diseases and pandemies. HIV and HCV chronic invaders, The most important lesson comes from the following great achievement it is possible to control a. chronic infection of a very sophisticated virus such as HIV that hides inside the chromosomes of the. infected cell Although the victory is not total yet it has profoundly changed the fate of the pandemic. victims at least in western countries After being inspired by other research fields anti HIV research. has infected other field of antiviral research and will continue to do so Remarkably after the. identification of HIV the control of HIV through antiretrovirals originated from a collective effort on a. wide variety of scientific and medical fields including efficient transfer from academia to the. corporate world More recently hepatitis C virus HCV research is now boosting the antiviral. chemotherapy field Viral polymerases and proteases are targets par excellence validated by the use. of inhibitors against HIV reverse transcriptase and protease hepatitis B polymerase and herpes virus. polymerase Anti HCV protease and polymerase inhibitors are in various stages of clinical trials. Novel targets and cognate inhIbitors are adding to the list such as the HIV integrase and the HCV. HCV genus Hepacivirus and DENV genus Flavivirus belong to the same viral family Flaviviridae. sharing similar genome organization and replication strategies Initially research conducted on dengue. virus DENV was the actual starting and inspiration point for HCV research when it became known. that HCV had a flavivirus like genome Presently and conversely knowledge and strategies gained. from the successful drug discovery and design process against HCV can now be translated back to the. DENV research field, SARS and Influenza H5N1 and H1N1 hit and run viruses. The SARS pandemic was due to a novel coronavirus which emerged in 2003 from China The virus. took the world by surprise as coronaviruses were not known to cause life threatening pathologies. Coronaviruses were clearly neglected viruses from the scientific and the medical veterinary point of. view The pandemic revealed blatantly our unpreparedness to such a problem point of care in. hospitals crowded with contagious patients high toll for clinicians tracing secondary contacts of taxi. drivers and plane passengers etc The pessimistic say that nowadays viruses travel around the world. in 3 days The optimistic say that social networks and cell phones make information travel much. faster Perhaps the true challenge is elsewhere making people believe and adhere to an official. information as exemplified with the recent H1N1 crisis and the unsuccessful vaccination campaign In. any case this crisis has been the best advocate for antivirals as a complementary strategy to. prEvention and vaccination, In the case of influenza the size of the market has been the main booster of anti influenza drug.
development This includes the availability of patients for clinical trials and the fact that a potential. devastating pandemic would undoubtedly provoke stockpiling of antivirals in the time window into. which an appropriate vaccine would available Advice to stockpile anti influenza drugs has been. recurrently advertised mostly after 1995 when the 1918 spanish influenza strain genome was. published 8 well before the H5N1 and the H1N1 fear hit the world. These two viruses do not produce chronic infections These types of virus produce an infection. unnoticed mild or acute which resolves with virus clearance This transient nature of the infection. has long been a problem to design an efficient therapeutic answer Indeed there are too many. unpredictable parameters to build a drug design program based on traditional planning and funding. approaches The two biggest problems are that it is impossible to evaluate precisely the market and. invest accordingly and that there is an unpredictable number of patients available for clinical trials. The instructive aspect of these pandemics however is that they greatly contributed to re shape. antiviral research at large how can we anticipate how money is going to be invested These recent. crises have shaped considerably the grand public opinion towards the necessity to have broad. spectrum anti influenza drugs ready,The methods used to discover antivirals. The original method of discovery of antivirals was partially a knowledge based method centered. around nucleobases and nucleosides eg uridine derivatives mentioned above against Herpes known. to be used by viruses for their replication The advent of AIDS and the discovery of non nucleoside. reverse transcriptase inhibitors opened the era of large scale screening which is entirely a trial and. error procedure not based on previous knowledge Millions of compounds are tested as fast as. possible using high throughput screening HTS techniques and only those showing activity are. Infected cell assays, In both cases Herpes and AIDS infected cell cultures provided the antiviral read out before purified. targets were available and could be used In these assays compounds are tested individually to see if. they either cure an infected cell or protect it from infection pathogenic effects The process is simple. and relies on a cell culture system able to support virus growth Not surprisingly the discovery of. antivirals parallels the establishment of a robust infected cell based assay When this was difficult or. even not possible eg HCV the use of sub genomic replicons or surrogate viruses has nevertheless. allowed drug discovery and design There are now a wide variety of assay systems specific for each. virus Robust dengue infected cell assays are available highly efficient in terms of characterizing the. potency of a drug candidate One significant disadvantage is the cost associated with cell culture. reagents and facilities especially in low income countries However this method has an impressive. record of success compared to other methods,Knowledge based methods. The general trend is to reduce this trial and error approach and inject knowledge as much as possible. in the selection process so as to reduce costs and increase efficiency. Computer aided structure activity relationship SAR studies facilitate a responsive and efficient. management of research results and programs Drug resistance must be considered as part of the drug. design process as drug resistance mechanisms are being increasingly characterized and drug. combinations optimized in order to avoid or delay resistance The first large scale effort to discover. anti DENV drugs is to be credited to the Novartis Institute of Tropical Diseases Singapore who. conducted a complete screen of their proprietary chemical library against the DENV protease domain. from non structural protein NS3 see below, Knowledge based methods differ from classical cell based screening techniques in that they use. screening or discovery systems characterized at the molecular and sometime atomic levels The. discovery system represents or approximates a given step of the virus life cycle The knowledge. associated with the system reduces the number of putative targets and is supposed to provide directly. a mechanism of action of the compound or candidate drug Examples of such systems are purified. enzymes used directly in the drug discovery test It is expected that inhibition of the enzyme by a. compound in a test tube will mimic inhibition of the enzyme in the context of a viral infection This is. of course not granted For a good enzyme inhibitor the most frequent reasons of failure to inhibit a. virus in a cellular context are,The compound does not penetrate inside the cell.
The compound is rapidly degraded metabolized transformed into an inactive compound. The compound is toxic and of poor selectivity ie when used in a cellular context the. compound will kill the infected cell and any direct effect on the virus is not apparent. Many compounds can be selected as good inhibitors of a viral enzyme However the majority will fail. to convert into a candidate drug for the above reasons. However the main advantages of the method are, it discovers both a compound and its target at the same time. Currently increasing general medicinal chemistry knowledge allows a better pre screening of. compounds that have potential ie chemical libraries used as the source of molecules are each. day better in terms of containing drug like molecules. The future is the integration of both cell based assays and knowledge based methods to reduce the. time involved in i finding the target at the molecular level ii having a trustable molecular atomic. model to go quickly into hit to lead development by medicinal chemistry. The source of anti infectious molecules, Before their antiviral properties are discovered antiviral chemicals or molecules either exist physically. somewhere in the world and are selected or discovered or they do not exist and are invented and. subsequently synthesized For molecules having a physical existence they are either owned by. someone and generally organized in a chemical library or repository or they are in the wild in. plants marine organisms insects etc The issue of final ownership ie of a discovered molecule. having interesting properties is then much more complicated. This is an important distinction that has wide implications in drug discovery from the ease of. discovery to the final ownership and availability to patients The source of antiviral molecules is. indeed a key issue particularly for dengue for two main reasons. The cost of a drug is going to be a main issue because dengue occurs majoritarily in low. income countries, Although the low income dengue afflicted countries generally do not have screening and drug. design facilities most of the potential natural sources of drugs mostly plants are located in. these countries,Chemical libraries, The availability of large collections of pure compounds that can be handled tested analyzed and. whose compounds can be re ordered has considerably evolved over the last decades These large. collections were initially exclusively found in large pharmaceutical companies Over the years these. companies had accumulated compounds assays and know how The situation has drastically changed. over the last decade mainly because robotics and bio chemo informatics have penetrated academic. modest in size labs and research structures It has long been argued that screening was an industrial. job best accomplished in a corporate setting an observation that was true to a certain extent because. sophisticated robotics engineering know how and manpower was more easily mobilized there The. Antiviral Research and Development Against Dengue Virus Bruno Canard PhD bruno canard afmb univ mrs fr 1 Table of Contents Part 1 Antivirals 3 A short historical view on antiviral research and therapies 3 Lessons learned from recent viral diseases and pandemies 3 The methods used to discover antivirals 4 Infected cell assays 5 Knowledge based methods 5 The source of anti infectious

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