Preclinical development of novel liver-stage active antimalarials with radical cure potential

In the past decade, the global malaria eradication campaign has propelled forward a surge in antimalarial drug development. However, many challenges remain for a sustainable elimination, including the failing effectiveness of front-line artemisinin-based combination therapy and safety concerns associated with limited radical cure options for relapsing malaria. With increasing multidrug resistance and the absence of a clinically proven vaccine, there is an urgent need and continuous search for novel, effective, affordable, and safe antimalarial drugs to overcome artemisinin resistance, and ideally, such agents would be efficacious in both treatment of active bloodstream infections and preventing the disease at the liver-stage before clinical manifestations occur.

Liver-stage is the first step of any natural malaria infection, a silent but obligatory phase before the onset of the clinical symptoms of disease, which makes it an attractive target for antimalarial prophylactic intervention strategies and vaccine development. Drugs targeting liver stage malaria offer many advantages over drugs that merely target the blood stage and most importantly, only liver-stage active drugs could provide the ability for a radical cure to prevent relapse malaria, caused by dormant parasites hibernating in host liver cells for long periods of time. This approach specifically aims to exploit the strengths of compounds with efficacy against liver-stage malaria, which is considered the “Achilles’ heel” in the life cycle of malaria parasites. A novel antimalarial chemotype has been developed with dual stage activity against both liver-stage and blood-stage malaria, as well as single-dose cure ability and potential to prevent relapsing malaria infection. The ability to combat multiple stages of the infection represents a powerful tool, and one ideally suited to achieve the broadest possible benefit as the malaria eradication effort proceeds.

Malaria remains one of the deadliest diseases in the world today and accounts for over 200 million clinical cases worldwide each year along with roughly half a million deaths, mostly children under the age of 5 and pregnant women. The overarching goal is to develop a novel antimalarial for both prevention and treatment that is safe in individuals with G6PD deficiency, and in the most vulnerable populations – pregnant women and children, thus supporting world-wide elimination of the disease. Given the scope of the global impact of malaria, the significance of success in these efforts would be nothing less than improving the lives of millions of individuals and the chance to change the fate of entire nations.

To develop the liver-stage active antimalarial acridones, a multi-institutional consortium with interdisciplinary expertise has been established. Significant progress has been made with this research project in the previous funding period. A large library of acridone derivatives has been synthesized, and a rigorous lead optimization strategy has produced lead candidates with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. The focus of the studies proposed in this application is to explore partnering drug candidates for maximizing radical cure potential, and to conduct extensive preclinical evaluations with a successful late lead candidate that ultimately can be advanced in human phase 1 and phase 2 clinical trials.

PSU News

Drug-based Strategies
Product Development

Jul 2022 — Jun 2026

$2.88M

United States