X-ray imaging of a target enzyme reveals a way to produce more efficient and effective medications against malaria
Malaria kills around 1.2 million people each year, and is accumulating resistance to current antimalarial drugs. Finding an effective medication against malaria is long overdue.
Yongyuth Yuthavong and colleagues at the National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand, together with scientists from across the world, recently developed a technique for creating highly efficient drugs that target specific enzymes present in different pathogens. Using this technique, they have produced a new antimalarial drug candidate, P218.
The main target for many antimalarial drugs is a form of dihydrofolate reductase (DHFR); in the malaria parasite Plasmodium it is called PfDHFR. Since PfDHFR constantly mutates, it has become resistant to antimalarial treatments.
“We studied the x-ray structure of mutant forms of the PfDHFR enzyme to understand how resistance arises,” explains Yuthavong. This work showed that the mutations cause PfDHFR to change its geometry, thereby restricting drug molecule activity.
Using the x-ray structures as a guide, the team designed P218 as an inhibitor that envelops the enzyme and binds so tightly that there is no space left for mutation. Further, P218 is shaped so that it will bind only to malarial PfDHFRs if they are present in the body, not human DHFRs, meaning it is less toxic to humans.
Yuthavong, Y., Tarnchompoo, B.,Vilaivan, T., Chitnumsub, P., Kamchonwongpaisan, S., Charman, S.A., McLennan, D.N., White, K.L., Vivas, L., Bongard, E., Thongphanchang, C., Taweechai, S., Vanichtanankul, J., Rattanajak, R., Arwon, U., Fantauzzi, P., Yuvaniyama, J., Charman, W.N. & Matthews, D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proceedings of the National Academy of Sciences USA 109, 16823–16828 (2012).
This article originally appeared on A-IMBN Research.
Posted on 12 March 2013