Saturday, March 22, 2014

New Molecule HSP90 discovered

  • A new molecule Heat Shock Protein 90 (HSP90) with potential to kill malaria parasite was discovered in the second week of March 2014. 
  • The new discovery could help in effective treatment of malaria. 
  • The discovery was made by the researchers from the University of Geneva led by Didier Picard.

  1. Team goal was to determine if there was a difference between the human form and the parasitic form of HSP90 and can be used for curative purposes.
  2. Team used sophisticated computerized model tools to characterize the various tridimensional conformations of the parasite’s HSP90. They found another pocket capable of binding inhibitory substances, completely absent in its human alter ego.
  3. Team used supercomputer to perform the screening of virtual library which contains more than a million chemical compounds and selected the five candidates which fit in the pocket of binding inhibitory substances. Virtual screening uses computer-based methods to discover new ligands (ions) on the basis of biological structures.
  4. The simulations were conducted to analyse the dynamics of interaction between the HSP90 and the candidate. This led to the discovery of inhibitors which interact specifically with the Plasmodium falciparum chaperone.
  5. Later the molecules were tested in vitro in different systems. The biologists demonstrated in particular the toxicity of those inhibitors on Plasmodium falciparum cultures, in sufficient doses to kill the parasites without affecting the infected red blood cells.

About HSP90
  • Hsp90 is a highly abundant and ubiquitous molecular chaperone which plays an essential role in many cellular processes including cell cycle control, cell survival, hormone and other signalling pathways. 
  • It is important for the cell's response to stress and is a key player in maintaining cellular homeostasis. In the last ten years, it has become a major therapeutic target for cancer, and there has also been increasing interest in it as a therapeutic target in neurodegenerative disorders, and in the development of anti-virals and anti-protozoan infections. 
  • The focus of this review is the structural and mechanistic studies which have been performed in order to understand how this important chaperone acts on a wide variety of different proteins (its client proteins) and cellular processes. 
  • As with many of the other classes of molecular chaperone, Hsp90 has a critical ATPase activity, and ATP binding and hydrolysis known to modulate the conformational dynamics of the protein. 
  • It also uses a host of cochaperones which not only regulate the ATPase activity and conformational dynamics but which also mediate interactions with Hsp90 client proteins. 
  • The system is also regulated by post-translational modifications including phosphorylation and acetylation. This review discusses all these aspects of Hsp90 structure and function.

Detail note about Malaria:
What is Malaria?
  • The word malaria comes from 18th century Italian malameaning "bad" and aria meaning "air". 
  • It was not until 1880 that scientists discovered that malaria was a parasitic disease which is transmitted by theanopheles mosquito. 
  • The mosquito infects the host with a one-cell parasite called plasmodium
  • By the end of the 18th century, scientists found out that Malaria is transmitted from person-to-person through the bite of the female mosquito, which needs blood for her eggs.

According to the World Health Organization(WHO):
    • Approximately 660,000 people died from malaria in 2010 globally, most of them were African children.
    • There were an estimated 219 million cases of malaria infection in 2010 worldwide.
    • Malaria is a preventable and curable disease.
    • Malaria mortality rates have fallen by over 25% since 2000. In the WHO African region rates have dropped by 33%.
    • The malaria burden in many parts of the world is being dramatically reduced thanks to increased malaria prevention and control measures.
    • Travelers from malaria-free areas who enter endemic areas are especially vulnerable to severe symptoms when they become infected.
    • About 80% of all malaria cases occur in just 17 countries.
    • Nigeria and the Democratic Republic of the Congo account for more than 40% of all malaria deaths worldwide.

    There are five types of malaria:

    • Plasmodium vivax (P. vivax) - milder form of the disease, generally not fatal. However, infected people still need treatment because their untreated progress can also cause a host of health problems. This parasite has a liver stage and can remain in the body for years without causing sickness. If the patient is not treated, the liver stage may re-activate and cause relapses - malaria attacks - after months, or even years without symptoms.

    • Plasmodium malariae (P. malariae) - milder form of the disease, generally not fatal. However, the infected human still needs treatment because no treatment can also lead to a host of health problems. This type of parasite has been known to stay in the blood of some people for several decades.

    • Plasmodium ovale (P. ovale) - milder form of the disease, generally not fatal. However, the infected human still needs to be treated because it may progress and cause a host of health problems. This parasite has a liver stage and can remain in the body for years without causing sickness. Without treatment there is a risk that the liver stage re-activates and cause relapses after very long periods without symptoms.

    • Plasmodium falciparum (P. faliparum) - the most serious form of the disease. It is most common in Africa, especially sub-Saharan Africa. Current data indicates that cases are now being reported in areas of the world where this type was thought to have been eradicated.

    • Plasmodium knowlesi (P. knowlesi) - causes malaria in macaques but can also infect humans.

    What are the symptoms of Malaria?

    In regions where Malaria is common, local people usually have some level of immunity, which means that many infected people may have no symptoms at all, or very few.
    Severity of Malaria symptoms depends on:
    1. The type of parasite.
    2. The individual's level of immunity.
    3. Whether the person still has his/her spleen.
    Early stage symptoms of Malaria
    • A high temperature (fever)
    • Chills
    • Headache
    • Sweats
    • Tiredness (fatigue)
    • Nausea
    • Vomiting
    Signs and symptoms tend to be cyclical in severity, during each wave levels of severity may differ. How long symptoms last may also vary, depending on each cycle. Early on during the disease, symptoms may not follow this pattern.
    Other common symptoms may include:
    • Dry cough
    • Back pain
    • Muscle ache
    • Enlarged spleen
    Very rare symptoms may include:
    • Impairment of brain function
    • Impairment of spinal cord function
    • Seizures (fits)
    • Loss of consciousness
    Patients infected with the P. falciparum parasite are more likely to become seriously ill - their illness can become life-threatening.

    What is the incubation period of Malaria?

    Incubation means the time between becoming infected and the appearance of symptoms. This generally depends on the type of parasite:
    • P. falciparum - 9 to 14 days
    • P. vivax - 12 to 18 days
    • P. ovale - 12 to 18 days
    • P. malariae - 18 to 40 days

    What are the treatment options for Malaria?

    According to WHO, in areas where Malaria is common treatment should start as soon as signs and symptoms appear, ideally within 24 hours.
    People with uncomplicated malaria can be treated as outpatients, while those with severe malaria need to be hospitalized.According to the CDC3, the following drugs are commonly used for treating malaria:
    • artemether-lumefantrine (Coartem®)
    • atovaquone-proguanil (Malarone®)
    • chloroquine
    • clindamycin (used in combination with quinine)
    • doxycycline (used in combination with quinine)
    • mefloquine (Lariam®)
    • quinidine
    • quinine
    • artesunate (not licensed for use in the United States, but available through the CDC malaria hotline 770-488-7100)

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