The Rothberg Institute for Childhood Diseases launches first international effort to fight Malaria

Guilford 13 November 2003The Rothberg Institute for Childhood Diseases (TRI), a non-profit research institute devoted to discovering medicines for orphan childhood diseases such as Tuberous Sclerosis Complex (TSC), has released the first Malaria target to an international community of more than 54.000 users from 93 countries currently running the Drug Design and Optimization Laboratory software (D2OL).

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D2OL is based on Sengent's CommunityOS, a Grid computing programme that harnesses idle time on volunteer computers from the on-line community to create a "supercomputer". This system is capable of using chemical docking algorithms and statistical models to rapidly test potential medicines against any potential target with a known crystal structure.

"While TRI focuses all of its laboratory efforts on making therapeutics to cure TSC, we see strong synergy in expanding our computational resources to support efforts directed towards emerging pathogens, bio-terrorism threats, and Third World diseases. This Malaria target was selected to help us test our methods while providing valuable results for the development of medicines against the parasite causing this devastating disease", stated Wolfgang Hinz, Senior Research Scientist at The Rothberg Institute for Childhood Diseases.

Results from this study can be used to prioritize the screening of drug-like compounds against the parasite and will be made freely available to the community and collaborating laboratories. Increasing resistance against previously successful therapeutics which targets the parasite in the blood stage of the life cycle prompted the scientists at TRI to select Plasmepsin II, a protease essential for the parasites survival in the red blood cell. Successful development of inhibitors of proteases, for example HIV-1 protease, further supports the choice of target.

Malaria is a life-threatening parasitic disease transmitted by the female Anopheles mosquito, which requires blood to nurture her eggs. Malaria causes or contributes to 3 million deaths and up to 500 million acute clinical cases each year. At least 40% of the world population, or an estimated 2,5 billion people in over 90 countries are at risk of becoming infected each year. The main risk areas are Africa, South East Asia, India and South America.

Risk groups include pregnant women, refugees, migrant workers, travellers to high risk areas and children. The majority of deaths are in children with a mortality rate of four children a minute or 35.000 children a week. Malaria was once widespread, but it was successfully eliminated or drastically reduced in 37 countries with temperate climates in the 1950's, in large part due to the WHO insecticide spraying programme between 1956-69.

This situation has been rapidly reversing, especially over the last decade. This reversing trend can be attributed to the cost of sustaining programmes, loss of motivation in the face of a seemingly declining threat, the development of insecticide resistance and resistance against existing treatments. Malaria parasites are developing unacceptable levels of resistance to one therapeutic after another and many insecticides are no longer useful against mosquitoes transmitting the disease. Years of vaccine research have produced few hopeful candidates and although scientists are redoubling the search, an effective vaccine may be years away.

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the presence of benign tumours, known as hamartomas, which occur in many tissues and organs including the brain, eyes, kidney, heart, lungs and skin. Hamartomas are lumps of disorganised, but differentiated cells, which in the case of TSC rarely progress to malignancy. During the first few years, the severity of TSC can range from mild skin abnormalities to severe epilepsy, mental retardation, autism, or attention deficit-hyperactivity disorder.

Three common and life threatening manifestations of the disease are renal Angiomyolypomas (AMLs), Lymphangioleiomyomatosis (LAM), and Subependymal Giant Cell Astrocytomas (SEGAs). TRI is therefore focusing its drug discovery efforts towards identifying compounds to treat these specific lesions. In recent years significant advances in the understanding of the underlying cause of TSC have been made. In particular the mutable genes (TSC1 and TSC2) responsible for the condition were identified and the role of their respective gene products (harmatin and tuberin) explored.

The CommunityTSC, also utilizing the D2OL software, project uses TSC-relevant proteins identified by sponsored collaborators at Harvard, Yale, and Fox Chase Cancer Center as therapeutic targets for computational screening. The targets are screened against all commercially available drug-like chemical entities - an estimated 2,5 million potential therapeutics - to prioritize the compounds to be tested in the laboratory both at TRI and collaborating academic institutions worldwide. To date, five targets have been identified and are currently screened by a user-community in excess of 18.000 members.

The Drug Design and Optimization Laboratory was established in November of 2001 to expedite and lower the cost of identifying therapeutics capable of addressing general health issues. The software was first applied to targets of potential bio-warfare/terrorism agents such as Anthrax and Smallpox. With the potential threat posed by emerging pathogens such as SARS, the use of D2OL was expanded specifically to protein targets of the SARS virus in May of 2003. TRI first applied D2OL to find a cure for TSC in April of 2002.

The Rothberg Institute operates at the intersection of modern biology, chemistry and computer science by leveraging technologies including chemical genomics and Grid computing to accelerate its medicine discovery efforts. Furthermore, The Rothberg Institute collaborates with academic laboratories at Yale, Harvard and the Fox Chase Cancer Institute through the Rothberg Award for Courage in Research administered by the TS-Alliance.

The latest version of D2OL used in the fight against emerging pathogens such as Malaria and SARS and potential bio-weapons such as Anthrax and Smallpox is available at the Drug Design and Optimization Lab Web site. More news on The Rothberg Institute can be found in the VMW October 2003 article Over 50.000 computers from 93 countries come together to combat SARS.


Leslie Versweyveld

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