The new project from University of South Florida has played a key role in yielding a promising new anti-malarial drug with the potential to cure the mosquito-borne disease and block its transmission with low doses. This innovative discovery was co-jointly done by Roman Manetsch, PhD, Associate Professor of Chemistry at University of South Florida, and Dennis Kyle, PhD, Professor of global health at University of South Florida. They developed a series of potent compounds to combat malaria known as the 4-(1H)-quinolone-3-diarylethers, or quinolones. These researchers were the part of a larger Medicines for Malaria Venture (MMV) project team including Oregon Health & Science University in Portland, Drexel University in Philadelphia, and Monash University in Australia. The researchers have narrowed their innovation to the most effective drug candidates in the quinolones series to one leading drug, ELQ-300. The clinical trial and approval of the drug has yet to be processed before launching the drug into the market.

In the initial preclinical trials done on animals, demonstrated the impressive preventive and transmission-blocking quality of the drug. Adding to this, the new drug (ELQ-300) is likely more cheaply than the existing antimalarial drugs. This is the major advantage in treating a tropical disease that kills nearly one million people per year and causes recurring bouts of severe and incapacitating illness, most often among poor people in the developing countries.
The new drug class identified by the researchers were derived from the first antimalarial drugs, like, quinolone, endochin, discovered more than 60 years ago but was never pursued as a treatment because it somehow not worked well in humans. Using the new technology to optimize the quinolones, the Medicines for Malaria Venture (MMV) project team demonstrated that these compounds were indeed highly effective against the the most lethal strain of malaria i.e. Plasmodium falciparum and Plasmodium vivax the major cause of malaria outside Africa. The quinolones target both the liver and blood stages of the parasite as well as the hinder the transmission of the disease. This is a challenging piece of work which requires years of hard work, toiling and collaboration across disciplines.

In humans, the malaria parasite enters the bloodstream through the bite of an infected mosquito and target the liver. Once it hit the liver, the infecting parasites replicate and rupture the liver cells, thus escaping back into the bloodstream. Though sometimes parasites can remain in the dormant state in the liver for a longer period of time. then these dormant parasites become active and attack the red blood cells, rapidly increasing its population which spread throughout the bloodstream in waves.

The researchers of the MMV team identified and refined the drug with a long half-life to prevent malaria and to offer long-term protection against the induced infection. It is a balancing act to optimize an antimalarial drug so that it become soluble and metabolically stable, without compromising with its potency. The compound would be introduced into the human and would not break down too quickly. It will circulate in the bloodstream for a longer period to kill the parasites and be highly active in blocking transmission.

The antimalarial drug is developed and designed to be potential enough to work without any harmful or bothersome side effects. The new drug, ELQ-300 targets a protein complex of the mitochondria that is integral for the energy household of a cell. This is a positive point when we are trying to incapacitate a malaria parasite's powerhouse, but the same hit in a human's mitochondria could be disastrous. So the quinolone scaffold was structurally modified so that the drug candidate ELQ-300 would selectively hit only the malaria parasite's target while sparing the human mitochondria.

With the rapid emergence of multi-drug resistant strains of malaria, the need to find new drugs capable of delaying or preventing drug resistance has become even more pressurizing. The quinolones, including ELQ-300, target the same biological pathway as atovaquone, the main component of Malarone, one of the newest combination drugs used to treat malaria. But, in repeated experiments ELQ-300 did not generate drug-resistant strains of the malaria parasite. Hence making it a significant improvement over atovaquone. In addition, the new drug's design makes it more effective at lower doses, hopefully meaning fewer and smaller pills for patients at a lower cost.

The drug is one of the first of its kind to kill the malaria parasite in all three stages of its life cycle. Thus, it may become part of a new-generation therapy that not only treats sick people and prevents them from getting ill, but also blocks the transmission of malaria from mosquitoes to humans. The drug has the capacity of breaking the parasite life cycle, which can ultimately help us in eradicating the disease.

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Geetanjali Murari
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