TY - JOUR
T1 - Small molecule inhibitors that selectively block dengue virus methyltransferase
AU - Lim, Siew Pheng
AU - Sonntag, Louis Sebastian
AU - Noble, Christian
AU - Nilar, Shahul H.
AU - Ng, Ru Hui
AU - Zou, Gang
AU - Monaghan, Paul
AU - Chung, Ka Yan
AU - Dong, Hongping
AU - Liu, Boping
AU - Bodenreider, Christophe
AU - Lee, Gladys
AU - Ding, Mei
AU - Chan, Wai Ling
AU - Wang, Gang
AU - Jian, Yap Li
AU - Chao, Alexander Theodore
AU - Lescar, Julien
AU - Yin, Zheng
AU - Vedananda, T. R.
AU - Keller, Thomas H.
AU - Shi, Pei Yong
PY - 2011/2/25
Y1 - 2011/2/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79953188722&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953188722&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.179184
DO - 10.1074/jbc.M110.179184
M3 - Article
C2 - 21147775
AN - SCOPUS:79953188722
SN - 0021-9258
VL - 286
SP - 6233
EP - 6240
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -