Next-Generation Peptide-Based Medicines for Malaria
Abstract
Malaria is a disease that causes episodes of fever and chills and can rapidly increase in severity, resulting in death. It is estimated that malaria has killed half of the people who have ever lived. Malaria is transmitted by Anopheles mosquitos, which transfer the disease-causing Plasmodium parasites from person to person. Concerted efforts to lessen the burden of malaria have included use of insecticidal sprays and impregnated bednets reduce mosquito numbers and night feeding, and development of antimalarial drugs to kill the parasites in their human host. These measures have been very effective. However, over 200 million people are still infected with malaria parasites every year with over 400 thousand of these infections resulting in death. Malaria parasites have developed resistance to every drug that has been developed. Current efforts to control the disease rely heavily on combination treatments that include the drug artemisinin, but parasites in South East Asia are developing resistance to this drug. This is alarming because South East Asia has been the epicenter for emergence and spread of parasites that developed resistance to other previously valuable drugs such as chloroquine. Malaria is a significant health concern to civilians in regions where malaria is present, but also a major consideration for military operations. The health status of military personnel who are deployed into regions with malaria impacts on the success of missions, and previous conflicts including World War II, the Korean War, and Vietnam collectively resulted in over 1.1 million personnel being infected with malaria. The threat of malaria impacts mission readiness for future deployment, making the prevention and treatment of this disease a serious concern for the U.S. Department of Defense and military partners. Modern methods to address malaria rely heavily on prevention, whereby preventative doses of antimalarial drugs must be taken regularly while personnel are stationed in the malaria-prevalent region, and for weeks afterward. Many antimalarial drugs have been associated with negative side effects, ranging from gastrointestinal upset and photosensitivity to significant neurological effects. Also, some antimalarial drugs, such as tafenoquine, are contraindicated for use in individuals with a particular enzyme deficiency. Curative doses of tafenoquine cause anemia in these people. The undesirable side effects associated with long-term use of preventative antimalarial drugs lessens the likelihood of deployed military personnel adhering to their prescribed drug regimens and increases the risk of developing serious disease. Considering the seriousness of malaria and the threat of losing the battle against emerging drug-resistant parasites, this project aims to develop a new class of molecule that kills malaria parasites via a different mechanism compared to all existing antimalarial drugs. To achieve this goal, we will harness the selective antimalarial activity of a peptide, or mini-protein, that we have developed from a small portion of a human blood protein called platelet factor 4 (PF4). We have stabilized the structure of this portion through a process called cyclization to produce a peptide with no exposed ends or undefined structures that could be degraded. This new molecule called cPF4PD (cyclic PF4 peptide dimer) can recognize and enter malaria-infected red blood cells (iRBCs) but does not enter or damage healthy cells. Once inside iRBCs, cPF4PD enters the malaria parasite and disrupts the parasite’s internal structure, resulting in weakened parasites. The safety profile and selective nature of cPF4PD makes it an ideal candidate for developing safer antimalarial drugs. The ability of cPF4PD to kill malaria parasites is promising, but this peptide needs to undergo some improvements to be useful as an antimalarial drug. Therefore, this project aims to develop improved versions of cPF4PD that are even more stable, so th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210219
Entities
People
- David Craik
Organizations
- United States Army
- University of Queensland