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168 Results for Members
Members
UCB research institutions, including the Henry Wheeler Center for Emerging and Neglected Diseases, provide a...
The University of California, San Diego (UCSD) is a research-focused public institution, with numerous...
UCSF focuses on conducting both basic and translational research, and played a key role in the development of...
UGA's Center for Tropical & Emerging Global Diseases (CTEGD) is built on a strong foundation in parasitology,...
The University is one of the largest recipients of federal government research grants in the country, and...
The University of South Florida is a high-impact, global research university. Faculty members in its...
175 Results for Collaborations
Collaborations
Dr. Siqueira-Neto was interested in screening phosphodiesterase (PDE) V inhibitors for activity against kinetoplastids and schistosomes, as one compound of this class showed activity against a Trypanosoma cruzi PDE involved in osmoregulation. BVGH connected Dr. Siqueira-Neto with Eisai, which provided a select set of PDEV inhibitors for Dr. Siqueira-Neto to screen in cell-based and enzyme-based assays against Trypanosoma, Brugia, Leishmania, and Schistosoma.
Dr. Keiser, Head of the Helminth Drug Development Unit at Swiss TPH, maintains in vitro and in vivo assays for a wide range of helminth life cycles. BVGH reviewed a publication detailing the effect of nicotinic acetylcholine receptor (nAChR) agonists on rat hookworm, and contacted Dr. Keiser to gauge her interested in screening related compounds. Dr. Keiser expressed interest, and Pfizer provided seven nAChR agonists that Dr. Keiser screened in her assays against Necator americanus, Ancylostoma ceylanicum, and Heligmosomoides polygyrus.
Soil-transmitted helminthiases, caused by multiple species of parasitic worms, affect more than 1.5 billion people, or nearly 25% of the world’s population. Dr. Keiser, Head of the Helminth Drug Development Unit at Swiss TPH, maintains in vitro and in vivo assays for a wide range of helminth life cycles. As part of its commitment to advancing global public health and accelerating discovery of new treatments for neglected diseases, J&J shared JNJ-46336173, a nicotinic acetylcholine receptor (nAChR) agonist, and over 100 analogs thereof, with Dr. Keiser through WIPO Re:Search. Dr. Keiser screened these compounds for activity against three parasitic helminth species.
Rates of drug-resistant TB are increasing, and treatments focused on new drug targets are desperately needed. One such potential target is MetAPs, which helps process proteins in Mycobacterium tuberculosis, the bacterium that causes TB. However, GSK’s initial efforts to develop inhibitors of the M. tuberculosis MetAP-1 enzyme were met with disappointing results. GSK shared its data with Dr. Ruminski and colleagues. As a result of this collaboration, CWHM revised its research priorities and placed the TB MetAP-1 inhibitor program on hold, saving an estimated three months of employee time and approximately $50,000 of research costs.
Phosphodiesterases (PDEs) are important regulators of cell signal transduction, and PDE inhibitors have been developed to treat various diseases, such as erectile dysfunction and chronic obstructive pulmonary disease (COPD). After reading reports that PDE inhibition in T. brucei, which causes HAT, led to parasite death, Dr. Pollastri and colleagues screened existing human PDE inhibitors for activity against T. brucei PDEs. When the team examined the inhibitors’ structure-activity relationships (SAR) — correlations between compound structures and activity against parasite PDEs —, it was difficult to discern clear trends or patterns, which slowed the compound optimization process significantly. BVGH connected Dr. Pollastri with scientists at Eisai who had experience working with PDE inhibitors. The scientists provided Dr. Pollastri with valuable advice on compound optimization, including suggestions for future approaches and experiments.
Resistance to current antimalarial drugs is a serious problem. New therapeutics with novel mechanisms of action are needed to curtail the suffering caused by malaria. Preliminary data from Dr. Gilbert and others suggested that a certain class of compounds might have antimalarial properties. Eisai shared proprietary compounds of that class with Dr. Gilbert to screen for activity against Malaria parasites.
171 Results for Assets
Assets
At the National Institute of Parasitic Diseases (NIPD), Dr. Jun-Hu Chen and others have developed a protein microarray that can be used for identifying bio-markers for potential use in malarial parasite diagnostics and vaccine development.
Dr. Xue-nian Xu’s group at the National Institute of Parasitic Diseases has developed the Cs1 rapid diagnostic immunochromatographic test strip for screening to find human patients infected with Chloriorciasis (Chinese liver fluke). Chinese liver fluke parasites reside in undercooked, smoked pickled and salted freshwater fish and infect humans who eat the fish. Dr Xu’s group is also developing a kit for the direct detection of the antigen of Chinese liver fluke. This kit might be able to detect liver fluke in uncooked fish. Dr. Xu is interested in collaborating with groups around these liver fluke diagnostic tests.
Unique antigenic domains of PfEMP1 a key parasite surface molecule implicated in development of severe malaria. Antibodies to these molecules stimulate cross strain immunity to both lab strains and clinical isolates of malaria parasites. These molecules could be effective targets for new therapeutic strategies to treat or prevent severe malaria. This technology is available from the University of Edinburgh for licence and/or research collaboration with a commercial partner able to support development of a treatment for severe malaria. - See more at: http://www.research-innovation.ed.ac.uk/Opportunities/Newantigensformal…
Severe malaria is linked to a process called rosetting in which malaria parasite-infected red blood cells form aggregates that block blood flow. in vital organs. Researchers have identified regions in 3 key gene variants of a molecule PfEMP1 that is key to forming these rosettes. Antibodies to these PfEMP1 regions show reactivity to diverse laboratory strains and clinical isolates of the malaria parasite. Optimised expression methods to permit production of antigens: In vivo evidence that targets are immunogenic, generate functional antibodies that block rosette formation and induce phagocytosis of infected red blood cells in vitro. Supportive data from clinical sera samples of children who do recover from malaria who have circulating Abs to these PfEMP1 types.
Targets the rosetting mechanism that underpins symptoms of severe malaria, thereby stopping adhesion of infected blood cells to blood vessels in major organs. Antibodies to these target antigens are cross-reactive, and the approach is effective against multiple parasite strains and, therefore, broadly applicable. It targets the most virulent forms of the malaria parasite, protecting and treat infected individuals, blocking progress of the disease.
Novel compound series of phosphofructokinase allosteric inhibitors which show excellent efficacy in vitro against the parasite and in mouse models of the disease in vivo. Only a short treatment time is required as those compounds kill the parasite faster than any reported so far. The inhibitors are safe and show favorable pharmacokinetic properties including oral bio-availability and ability to cross the blood brain barrier. The well-characterized inhibitors of this novel
trypanosomiasis target have the potential to fill the unmet need for safe, cheap, easily administered drugs with short course for treatment for African trypanosomiasis.
OPPORTUNITY
African Trypanosomiasis is a neglected tropical disease caused by 2 subspecies Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. It develops in 2 distinct stages with the 1st, body stage, resulting in cold-like symptoms and the 2nd, central nervous system stage, characterised by severe neurological symptoms. It is fatal if left untreated. It is most prevalent in economically disadvantaged rural communities in Africa which have little health infrastructure. Existing treatments are only available intravenously or are subspecies specific. Moreover, they often have severe side effects, long treatment duration, drug resistance and are expensive. There is therefore an urgent need for new effective and easily administered drugs.
TECHNOLOGY OVERVIEW
Phosphofructokinase (PFK) is an enzyme in the glycolytic pathway which converts fructose 6-monophosphate to fructose 1, 6-biphosphate on the cascade of converting glucose to pyruvate and ATP. Glycolysis is the sole source of ATP for the bloodstream form of the parasite and blocking it has been shown to kill the parasite much faster than any other drug mechanism. These compounds target the allosteric binding site on the parasite PFK which locks the enzyme in an inactive state. This allosteric pocket is unique to parasite PFK, therefore human phosphofructokinase is completely unaffected by the compounds minimising side effects. The drugs have been extensively characterised both in vitro and in vivo in terms of selectivity, potency and pharmacokinetics and show very favourable properties. Moreover, Trypanosoma brucei’s phosphofructokinase enzyme - compounds interaction have been very well studied by numerous crystal structures which would allow them to be easily modified to further improve properties.
Names of infectious Organisms: Trypanosoma brucei
Vector: Tsetse Flies
Human Target Organs: Blood /Lymph system in phase 1: CNS in phase 2
Mechanism of Action: Inhibition of key enzyme in the glycolytic pathway of the parasite
Molecular or Cellular Target Names: Phosphofructokinase (PFK)
BENEFITS
Novel validated target, well characterised mechanism of action and excellent structure-activity relationship
Compounds effective against both subspecies of the parasite and both stages of the disease
Orally bioavailable and able to cross the blood brain barrier in favourable proportions
Safe and effective in a mouse model with very short treatment duration (1-2 days)
Very fast time to completely kill the parasite (minutes vs days for other drug classes)
Can be used in combination with current medicines as they have a different mechanism of action
Sub-micro- molar activity against enzyme target PFK
Selectivity for trypanosomal over human PFK
Rapid and effective growth inhibition activity against parasites that cause HAT - Trypanosoma brucei rhodesiense and gambiense
In vivo efficacy in 2 mouse models of trypanosomiasis after single dose
Blood Brain Barrier penetration
Favourable ADME profile
Confirmed mechanism of action (ie enzyme inhibition correlates with level of parasite killing)
Known SAR, X-ray crystal structures of compounds bound to tPFK available to guide further rapid optimisation
PUBLICATION
ACS Med. Chem. Lett. 2014, 5, 12−17
Biophys J 2015, 109, 1149-1156
All vaccines that contain aluminum hydroxide or aluminum phosphate as an adjuvant (by far the most common adjuvants in the world) are susceptible to damage if accidentally frozen. Exposure to freezing temperatures occurs frequently in vaccine distribution systems due to poorly controlled refrigerators, use of frozen ice packs, and exposure to freezing ambient conditions. The technology that has been developed involves the use of formulation excipients that can protect vaccines from loss of potency due to freezing. These excipients are inexpensive, commonly used in pharmaceutical products, and included on the FDA list of excipients that are "Generally Regarded As Safe" (GRAS).
The University of Buea has experience of investigating crude plant extracts for selective activity in the search for novel filaricides.