Promising compound rapidly eliminates malaria parasite

December 05, 2014

(MEMPHIS, Tenn. - December 5, 2014) An international research collaborative has determined that a promising anti-malarial compound tricks the immune system to rapidly destroy red blood cells infected with the malaria parasite but leave healthy cells unharmed. St. Jude Children's Research Hospital scientists led the study, which appears in the current online early edition of the Proceedings of the National Academy of Sciences (PNAS).

The compound, (+)-SJ733, was developed from a molecule identified in a previous St. Jude-led study that helped to jumpstart worldwide anti-malarial drug development efforts. Malaria is caused by a parasite spread through the bite of an infected mosquito. The disease remains a major health threat to more than half the world's population, particularly children. The World Health Organization estimates that in Africa a child dies of malaria every minute.

In this study, researchers determined that (+)-SJ733 uses a novel mechanism to kill the parasite by recruiting the immune system to eliminate malaria-infected red blood cells. In a mouse model of malaria, a single dose of (+)-SJ733 killed 80 percent of malaria parasites within 24 hours. After 48 hours the parasite was undetectable.

Planning has begun for safety trials of the compound in healthy adults.

Laboratory evidence suggests that the compound's speed and mode of action work together to slow and suppress development of drug-resistant parasites. Drug resistance has long undermined efforts to treat and block malaria transmission.

"Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose," said corresponding author R. Kiplin Guy, Ph.D., chair of the St. Jude Department of Chemical Biology and Therapeutics. "These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude."

Whole genome sequencing of the Plasmodium falciparum, the deadliest of the malaria parasites, revealed that (+)-SJ733 disrupted activity of the ATP4 protein in the parasites. The protein functions as a pump that the parasites depend on to maintain the proper sodium balance by removing excess sodium.

The sequencing effort was led by co-author Joseph DeRisi, Ph.D., a Howard Hughes Medical Institute investigator and chair of the University of California, San Francisco Department of Biochemistry and Biophysics. Investigators used the laboratory technique to determine the makeup of the DNA molecule in different strains of the malaria parasite.

Researchers showed that inhibiting ATP4 triggered a series of changes in malaria-infected red blood cells that marked them for destruction by the immune system. The infected cells changed shape and shrank in size. They also became more rigid and exhibited other alterations typical of aging red blood cells. The immune system responded using the same mechanism the body relies on to rid itself of aging red blood cells.

Another promising class of antimalarial compounds triggered the same changes in red blood cells infected with the malaria parasite, researchers reported. The drugs, called spiroindolones, also target the ATP4 protein. The drugs include NITD246, which is already in clinical trials for treatment of malaria. Those trials involve investigators at other institutions.

"The data suggest that compounds targeting ATP4 induce physical changes in the infected red blood cells that allow the immune system or erythrocyte quality control mechanisms to recognize and rapidly eliminate infected cells," DeRisi said. "This rapid clearance response depends on the presence of both the parasite and the investigational drug. That is important because it leaves uninfected red blood cells, also known as erythrocytes, unharmed."

Laboratory evidence also suggests that the mechanism will slow and suppress development of drug-resistant strains of the parasite, researchers said.

Planning has begun to move (+)-SJ733 from the laboratory into the clinic beginning with a safety study of the drug in healthy adults. The drug development effort is being led by a consortium that includes scientists at St. Jude, the Swiss-based non-profit Medicines for Malaria Venture and Eisai Co., a Japanese pharmaceutical company.
The first author of this study is Maria Belen Jimenez-Diaz of GlaxoSmithKline, Madrid. The other authors are Daniel Ebert, Jonathon Diep, Greg Fedewa, Jeremy Horst and Charles Kim, all of University of California, San Francisco; Yandira Salinas, Julie Clark, Armand Guiguemde, Gloria Holbrook, Martina Sigal and Anang Shelat, all of St. Jude; Angela Carillo, Amy Matheny, Gregory Miller and Fangyi Zhu, all formerly of St. Jude; Anupam Pradhan and Dennis Kyle, both of University of South Florida, Tampa; Adele Lehane, Adelaide Dennis, Natalie Spillman and Kiaran Kirk, all of Australian National University, Canberra; Marie-Eve Myrand-Lapierre, Xiaoyan Deng and Hongshen Ma, all of University of British Columbia, Vancouver, Canada; Kathleen O'Loughlin, Aaron Endsley and Jon Mirsalis, all of SRI International, Menlo Park, Calif.; David Shackleford and Susan Charman, both of Monash University, Parkville, Australia; Mariana Justino Lage de Almeida, Marcus C.S. Lee and David Fidock, all of Columbia University Medical Center, New York, N.Y.; Sandra Duffy and Vicky Avery, both of Griffith University, Brisbane, Australia; Maria Garcia Gomez-Lorenzo, Maria Santos Martinez, Ane Rodriguez-Alejandre, Laura Sanz, Francisco Javier Gamo, Santiago Ferrer and Inigo Angulo-Barturen, all of GlaxoSmithKline; Jian Liu, Phillip Stein, Zheng Wang, Spencer Knapp and David Floyd, all of Rutgers University, Piscataway, N.J.; and David Waterson, Medicines for Malaria Venture, Geneva, Switzerland.

The research was funded in part by a contract (N2722011000221) from the National Institutes of Allergy and Infectious Diseases, which is part of the National Institutes of Health (NIH); grants (AI090662, AI075517) from the NIH; Medicines for Malaria Venture; Australian National Health and Medical Research Council Project Grant 1042271 and Overseas Biomedical Fellowships; Howard Hughes Medical Institute; The David and Lucille Packard Foundation; and ALSAC.

St. Jude Media Relations Contacts

Carrie Strehlau
desk (901) 595-2295
cell (901) 297-9875

Summer Freeman
desk (901) 595-3061
cell (901) 297-9861

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20 percent to 80 percent since the hospital opened more than 50 years ago. St. Jude is working to increase the overall survival rate for childhood cancer to 90 percent in the next decade. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food--because all a family should worry about is helping their child live. To learn more, visit or follow St. Jude at @stjuderesearch.

St. Jude Children's Research Hospital

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to