Scientists are developing a new antimalarial drug with a novel mechanism of action which shows promise for clearing a Plasmodium (malaria parasite) infection after a single dose, according to an article published in the journal Science. Scientists say the antimalarial candidate, called spiroindolone NITD609 has a novel compound and will most likely be the next generation for drug resistant malaria.

The authors write that spiroindolone NITD609 is effective against both Plasmodium (P.) falciparum and P. vivax - two malaria parasite strains. It clears plasmodium in a malaria mouse rapidly, the researchers say, and will probably work on humans with just a once-daily dosing regimen.

There are about 247 million human cases of malaria worldwide annually, according to WHO (World Health Organization), of whom approximately 1 million die. The majority of deaths from malaria are children in Africa. This preventable and curable illness is estimated to kill a child every 45 seconds in Africa alone. Not only is Malaria associated with poverty, it is also a cause of poverty and an important obstacle to economic development.

Mark Fishman, president, Novartis Institutes for BioMedical Research, said:

Malaria remains a scourge. The parasite has demonstrated a frustrating ability to outwit new medicines, from quinine to today's unsettling increased tolerance to artemisinin derivatives. We are delighted that our scientists could provide this potential new malaria therapy, based on an unprecedented chemical structure and directed to a novel target.

The authors write that if ongoing regulatory pharmacological and safety studies go according to plan, spiroindolone NITD609 will most likely progress to Phase I human trials. A Novel Mechanism of Action The identification and validation of new antimalarials drugs has proven challenging, despite considerable advances in Plasmodium genome biology, the researchers explain. With spiroindolone NITD609, they say they have found a potential target by identifying mutations that undermine the parasite's sensitivity to this new class of compound.

Novartis Institute for Tropical Disease's Bryan Yeung, project team head, said:

Using a novel Plasmodium whole-cell assay we were able to tap into the Novartis archive of 12,000 pure natural products and synthetic compounds to identify 275 compounds highly active against P. falciparum, the most prevalent and deadly form of malaria. From this set all but 17 compounds were discarded for failing to meet pharmacological and efficacy standards.

Of the remaining compound class, spirotetrahydro-beta-carbolines or spiroindolones have favorable physical and chemical properties for drug development as well as a mechanism of action distinct from the currently used therapies based on aminoquinolines and artemisinin derivatives.

The novel compound of spiroindolone NITD609 has been the result of a collaboration between the Genomics Institute of the Novartis Research Foundation (GNF), the Swiss Tropical and Public Health Institute and The Scripps Research Institute, and major support by The Wellcome Trust, the Medicines for Malaria Venture (MMV), A*STAR, Singapore and the US government. What is Malaria? It was not until 1880 that scientists discovered that malaria was a parasitic disease which is transmitted by the anopheles mosquito. The mosquito infects the host with a one-cell parasite called plasmodium. Not long after they found out that Malaria is transmitted from human-to-human through the bite of the female mosquito, which needs blood for her eggs.

Approximately 40% of the total global population is at risk of Malaria infection. During the 20th century the disease was effectively eliminated in the majority of non-tropical countries.

How does infection occur? The female Anopheles mosquito transmits the parasite to a human when it bites a person in order to feed on blood. Only the female mosquito can transmit malaria, and it must have been infected when it had previously bitten an infected human. When the mosquito bites an infected person a tiny quantity of the malaria (plasmodium) parasite in the blood is taken. Approximately one week later that same infected mosquito takes its next blood meal. The plasmodium parasites mix with the mosquito's saliva and are injected into the host (human being).

How can human-to-human transmission of malaria occur? As the parasite exists in human red blood cells, malaria can be passed on from one person to the next through organ transplant, shared use of needles/syringes, and blood transfusion. An infected mother may also pass malaria on to her baby during delivery (birth) - this is called 'congenital malaria'.

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 type has the widest geographic distribution globally. About 60% of infections in India are due to P. vivax. 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. 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 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. Click here to read a more comprehensive article on malaria.

"Spiroindolones, a Potent Compound Class for the Treatment of Malaria"
Matthias Rottmann,, Case McNamara, Bryan K. S. Yeung, Marcus C. S. Lee, Bin Zou, Bruce Russell, Patrick Seitz, David M. Plouffe, Neekesh V. Dharia, Jocelyn Tan, Steven B. Cohen, Kathryn R. Spencer, Gonzalo E. González-Páez, Suresh B. Lakshminarayana, Anne Goh, Rossarin Suwanarusk, Timothy Jegla, Esther K. Schmitt, Hans-Peter Beck, Reto Brun, Francois Nosten, Laurent Renia, Veronique Dartois, Thomas H. Keller, David A. Fidock, Elizabeth A. Winzeler, Thierry T. Diagana
Science 3 September 2010: Vol. 329. no. 5996, pp. 1175 - 1180
DOI: 10.1126/science.1193225

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