Naturally occurring cobalamins have antimalarial activity

Area of Science:

• Biochemistry
• Parasitology
• Medicinal Chemistry

Background:

• Antimalarial drug resistance necessitates novel chemotherapeutic agents.
• Beta-haematin (synthetic haemozoin) formation is a critical target for antimalarial drugs.
• Vitamin B12 (cobalamin) derivatives are explored for their potential antimalarial activity.

Purpose of the Study:

• To evaluate the inhibitory effects of vitamin B12 derivatives on beta-haematin formation.
• To compare the efficacy of cobalamins with chloroquine in inhibiting haemozoin formation.
• To investigate the antimalarial activity and food vacuole accumulation of cobalamins.

Main Methods:

• Assessed beta-haematin formation inhibition by various cobalamins (Adenosylcobalamin, Methylcobalamin, Aquocobalamin, Cyanocobalamin) and chloroquine.
• Determined antimalarial activity of cobalamins in vitro.
• Investigated cobalamin accumulation in the Plasmodium falciparum food vacuole via pH trapping.

Main Results:

• Adenosylcobalamin, Methylcobalamin, and Aquocobalamin were ~40 times more effective inhibitors of beta-haematin formation than chloroquine.
• Cyanocobalamin showed slightly greater inhibition than chloroquine; dicyanocobinamide had no effect.
• Cobalamins exhibit antimalarial activity, with Adenosylcobalamin > Methylcobalamin > Aquocobalamin > Cyanocobalamin, though less than chloroquine or quinine.
• Aquocobalamin accumulates in the parasite food vacuole by pH trapping, unlike other tested cobalamins.

Conclusions:

• Vitamin B12 derivatives, particularly Adenosylcobalamin and Methylcobalamin, are potent inhibitors of beta-haematin formation.
• Cobalamins demonstrate antimalarial properties by interfering with haemozoin synthesis.
• Targeting the unique cobalamin-dependent methionine synthase in Plasmodium falciparum offers a potential strategy for novel antimalarial drug development.