The Journal of biological chemistry · 2010
Small molecule inhibitors that selectively block dengue virus methyltransferase.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Lim Siew Pheng, Sonntag Louis Sebastian, Noble Christian, Nilar Shahul H, Ng Ru Hui, Zou Gang, Monaghan Paul, Chung Ka Yan, Dong Hongping, Liu Boping, Bodenreider Christophe, Lee Gladys, Ding Mei, Chan Wai Ling, Wang Gang, Jian Yap Li, Chao Alexander Theodore, Lescar Julien, Yin Zheng, Vedananda T R, Keller Thomas H, Shi Pei-Yong
Аннотация
Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.