Transition state analogs are chemical compounds with a chemical structure that resembles the transition state of a substrate molecule in an enzyme-catalyzed chemical reaction. Transition state analogs usually do not undergo a chemical reaction and can act as enzyme inhibitors by blocking their active site.
Investigators at the Albert Einstein College of Medicine (New York, NY, USA) worked with a small group of Aotus monkeys, which normally die as the result of P. falciparum infection. In the current study, after infection with the malaria parasite the monkeys were treated with the experimental drug BCX4945 (DADMe-Immucillin-G). This drug – a member of the transition analog class of reagents – acts by blocking the activity of the enzyme purine nucleoside phosphorylase (PNP). PNP is used by P. falciparum to manufacture the purine precursor hypoxanthine, which the parasites use to make DNA.
Results published in the November 11, 2011, online edition of the journal PLoS ONE revealed that oral administration of BCX4945 for seven days resulted in parasite clearance in otherwise lethal infections of P. falciparum in Aotus monkeys. Withholding the drug caused the parasites to reappear. BCX4945 caused depletion of hypoxanthine from the monkeys’ blood, demonstrating inhibition of both human and malarial PNP in vivo. The molecular action of BCX4945 was demonstrated in crystal structures of human and P. falciparum PNPs.
The efficacy, oral availability, chemical stability, unique mechanism of action, and low toxicity of BCX4945 demonstrate the potential for use of this drug in combination therapies with other antimalarial agents.
“Inhibiting PNP differs from all other current approaches for treating malaria,” said senior author Dr. Vern Schramm, professor of biochemistry at the Albert Einstein College of Medicine. “For that reason, BCX4945 fits well with the current World Health Organization protocols for malaria treatment, which call for using combination-therapy approaches against the disease.”
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