학술논문

KAF156 Is an Antimalarial Clinical Candidate with Potential for Use in Prophylaxis, Treatment, and Prevention of Disease Transmission
Document Type
article
Source
Antimicrobial Agents and Chemotherapy. 58(9)
Subject
Medical Microbiology
Biomedical and Clinical Sciences
Clinical Sciences
HIV/AIDS
Orphan Drug
Infectious Diseases
Vector-Borne Diseases
Rare Diseases
Malaria
Prevention
Development of treatments and therapeutic interventions
5.1 Pharmaceuticals
Infection
Good Health and Well Being
Animals
Antimalarials
Imidazoles
Inhibitory Concentration 50
Malaria
Falciparum
Mice
Mice
Inbred ICR
Piperazines
Plasmodium falciparum
Sporozoites
Microbiology
Pharmacology and Pharmaceutical Sciences
Medical microbiology
Pharmacology and pharmaceutical sciences
Language
Abstract
Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.