Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa.
Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50's of 1.3 and 27 microM, respectively. A crystal structure of protein-inhibitor (clavatadine A) complex was obtained and revealed interesting selective binding and irreversible inhibition of factor XIa. The cocrystal structure provides guidance for the design and synthesis of future factor XIa inhibitors as antithrombotic agents.
Eskitis Institute, Griffith University, Brisbane, Queensland 4111, Australia.
Malcolm S
MS
Buchanan
Anthony R
AR
Carroll
Deborah
D
Wessling
Michael
M
Jobling
Vicky M
VM
Avery
Rohan A
RA
Davis
Yunjiang
Y
Feng
Yafeng
Y
Xue
Linda
L
Oster
Tomas
T
Fex
Johanna
J
Deinum
John N A
JN
Hooper
Ronald J
RJ
Quinn
D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification*; D005591:Chemical Fractionation; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000302:isolation & purification*; D006146:Guanidines / Q000737:chemistry / Q000302:isolation & purification*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010648:Phenylacetates / Q000737:chemistry / Q000302:isolation & purification*; D011161:Porifera / Q000737:chemistry*
D001688:Biological Products; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D006146:Guanidines; D010648:Phenylacetates; C531075:clavatadine A; D015951:Factor Xa