Drug Discovery for Neglected Diseases: View of A Public–Private Partnership

Don, Robert; Chatelain, Eric

doi:10.1002/9783527626816.ch3

Cited by 10 publications

(12 citation statements)

References 15 publications

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“…Thankfully, with the investment of funds from organizations such as the Bill and Melinda Gates Foundation, Medicines for Malaria Venture (MMV), the Drugs for Neglected Diseases initiative (DNDi), and the Institute for One World Health (IOWH) this scenario is changing [47], [48]. Now, pharmaceutical giants such as Novartis [49], GSK [50], Pfizer (just to name a few) investing great efforts in the development of novel antimalarials (www.mmv.org/research-development/science-portfolio).…”

Section: Introductionmentioning

confidence: 99%

Functional Expression of Parasite Drug Targets and Their Human Orthologs in Yeast

et al. 2011

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BackgroundThe exacting nutritional requirements and complicated life cycles of parasites mean that they are not always amenable to high-throughput drug screening using automated procedures. Therefore, we have engineered the yeast Saccharomyces cerevisiae to act as a surrogate for expressing anti-parasitic targets from a range of biomedically important pathogens, to facilitate the rapid identification of new therapeutic agents.Methodology/Principal FindingsUsing pyrimethamine/dihydrofolate reductase (DHFR) as a model parasite drug/drug target system, we explore the potential of engineered yeast strains (expressing DHFR enzymes from Plasmodium falciparum, P. vivax, Homo sapiens, Schistosoma mansoni, Leishmania major, Trypanosoma brucei and T. cruzi) to exhibit appropriate differential sensitivity to pyrimethamine. Here, we demonstrate that yeast strains (lacking the major drug efflux pump, Pdr5p) expressing yeast (ScDFR1), human (HsDHFR), Schistosoma (SmDHFR), and Trypanosoma (TbDHFR and TcDHFR) DHFRs are insensitive to pyrimethamine treatment, whereas yeast strains producing Plasmodium (PfDHFR and PvDHFR) DHFRs are hypersensitive. Reassuringly, yeast strains expressing field-verified, drug-resistant mutants of P. falciparum DHFR (Pfdhfr 51I,59R,108N) are completely insensitive to pyrimethamine, further validating our approach to drug screening. We further show the versatility of the approach by replacing yeast essential genes with other potential drug targets, namely phosphoglycerate kinases (PGKs) and N-myristoyl transferases (NMTs).Conclusions/SignificanceWe have generated a number of yeast strains that can be successfully harnessed for the rapid and selective identification of urgently needed anti-parasitic agents.

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Section: Introductionmentioning

confidence: 99%

Functional Expression of Parasite Drug Targets and Their Human Orthologs in Yeast

et al. 2011

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“…This centralized and disease-focused LO model also facilitated effective project management by DNDi, since each team in these LO consortia is dedicated to and accountable for the progress towards the goal of producing drug candidates that meet the TPP. Stable collaborative relationships between research teams within each of the LO programs, and a shared commitment to a common neglected disease target, create a positive working environment [12]. This LO model has proven to be successful and led to the identification of SCYX-7158, a drug candidate from the unique boron-containing oxaborole series originating from Anacor and optimized by the HAT LO Consortium that included SCYNEXIS Inc., Pace University (USA) and the Swiss Tropical and Public Health Institute.…”

Section: The Current Lo Model Adopted By the Dndimentioning

confidence: 99%

Drugs for Neglected Diseases Initiative Model of Drug Development for Neglected Diseases: Current Status and Future Challenges

Ioset

Chang

2011

Future Med. Chem.

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The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

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“…Diethylcarbamazine (DEC-CIT) citrate is one of the most widely used drugs in the treatment of FL. However, very little information about its solid-state characteristics can be found in the literature [1][2][3] . In a previous study we crystallized and analyzed DEC-CIT by thermal methods, vibrational and X-ray diffraction, revealing three phase transitions at low temperatures, resulting in changes in its molecular structure [4] .…”

Section: Polymorphs Of Some Common Drugs and Bioactive Agentsmentioning

confidence: 99%

“…Graphene is a nanostructure with unique physical properties that can be used to prepare a number of novel functional materials [1]. Bulk-quantities of graphene can be produced by exfoliation of expanded graphite with ultrasounds [2].…”

mentioning

confidence: 99%

High throughput crystallization of orcinol with various N-acceptor coformers: an alternative approach for exploring the structural landscape

Thakur¹,

Grobelny²,

Mukherjee³

et al. 2011

Acta Cryst Sect A

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Drug Discovery for Neglected Diseases: View of A Public–Private Partnership

Cited by 10 publications

References 15 publications

Functional Expression of Parasite Drug Targets and Their Human Orthologs in Yeast

Functional Expression of Parasite Drug Targets and Their Human Orthologs in Yeast

Drugs for Neglected Diseases Initiative Model of Drug Development for Neglected Diseases: Current Status and Future Challenges

High throughput crystallization of orcinol with various N-acceptor coformers: an alternative approach for exploring the structural landscape

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