[Structural biology for developing antimalarial compounds].

Abstract

The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of this malaria parasite resistant to conventional drug therapy has stimulated the search for antimalarial compounds with novel modes of action. Here the structure-function relationship studies for two Plasmodium proteins are presented. One example is the structural studies for S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum (PfSAHH) and the other example is those for 1-deoxy-D-xylulose reductoisomerase from Plasmodium falciparum (PfDXR). In the former study, the clue for design of species specific PfSAHH inhibitors was obtained by the structural comparison of the active site of PfSAHH with that of human SAHH (HsSAHH). Our study revealed that the inhibitor selectivity depends on the difference of only one amino acid residue in the active site; Cys59 in PfSAHH vs. Thr60 in HsSAHH. In the latter study, the inhibition of PfDXR enzyme by fosmidomycin has proved to be efficient in the treatment of uncomplicated malaria in recent clinical trials conducted in Gabon and Thailand. Our crystal structure analyses of PfDXR/inhibitor complexes revealed the molecular basis of fosmidomycin's action in P. falciparum. We expect that the structure-function relationship studies on Plasmodium proteins are useful for developing the more effective antimalarial compounds.

• Authors: Nobutada Tanaka, Tomonobu Umeda, Yoshio Kusakabe, Masayuki Nakanishi, Yukio Kitade, Kazuo T Nakamura
• Journal: Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi) Vol. 133 Issue 5 Pg. 527-37 ( 2013) ISSN: 1347-5231 [Electronic] Japan
• PMID: 23649394 (Publication Type: English Abstract, Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antimalarials
• Enzyme Inhibitors
• Fosfomycin
• Threonine
• fosmidomycin
• 1-deoxy-D-xylulose 5-phosphate reductoisomerase
• Adenosylhomocysteinase
• Aldose-Ketose Isomerases
• Cysteine

Topics

• Adenosylhomocysteinase (antagonists & inhibitors)
• Aldose-Ketose Isomerases (antagonists & inhibitors)
• Animals
• Antimalarials (chemistry, therapeutic use)
• Catalytic Domain
• Clinical Trials as Topic
• Crystallization
• Crystallography
• Cysteine
• Drug Design
• Enzyme Inhibitors (chemistry)
• Fosfomycin (analogs & derivatives, therapeutic use)
• Humans
• Molecular Conformation
• Plasmodium falciparum (enzymology, genetics)
• Protein Structure, Tertiary
• Structure-Activity Relationship
• Threonine