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.
Buchanan
Malcolm S
MS
Eskitis Institute, Griffith University, Brisbane, Queensland 4111, Australia.
Carroll
Anthony R
AR
Wessling
Deborah
D
Jobling
Michael
M
Avery
Vicky M
VM
Davis
Rohan A
RA
Feng
Yunjiang
Y
Xue
Yafeng
Y
Oster
Linda
L
Fex
Tomas
T
Deinum
Johanna
J
Hooper
John N A
JN
Quinn
Ronald J
RJ
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