PMID- 24844380
OWN - NLM
STAT- MEDLINE
DCOM- 20140820
LR  - 20211021
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 57
IP  - 11
DP  - 2014 Jun 12
TI  - Designing allosteric inhibitors of factor XIa. Lessons from the interactions of 
      sulfated pentagalloylglucopyranosides.
PG  - 4805-18
LID - 10.1021/jm500311e [doi]
AB  - We recently introduced sulfated pentagalloylglucopyranoside (SPGG) as an 
      allosteric inhibitor of factor XIa (FXIa) (Al-Horani et al., J. Med Chem. 2013, 
      56, 867-878). To better understand the SPGG-FXIa interaction, we utilized eight 
      SPGG variants and a range of biochemical techniques. The results reveal that 
      SPGG's sulfation level moderately affected FXIa inhibition potency and 
      selectivity over thrombin and factor Xa. Variation in the anomeric configuration 
      did not affect potency. Interestingly, zymogen factor XI bound SPGG with high 
      affinity, suggesting its possible use as an antidote. Acrylamide quenching 
      experiments suggested that SPGG induced significant conformational changes in the 
      active site of FXIa. Inhibition studies in the presence of heparin showed 
      marginal competition with highly sulfated SPGG variants but robust competition 
      with less sulfated variants. Resolution of energetic contributions revealed that 
      nonionic forces contribute nearly 87% of binding energy suggesting a strong 
      possibility of specific interaction. Overall, the results indicate that SPGG may 
      recognize more than one anion-binding, allosteric site on FXIa. An SPGG molecule 
      containing approximately 10 sulfate groups on positions 2 through 6 of the 
      pentagalloylglucopyranosyl scaffold may be the optimal FXIa inhibitor for further 
      preclinical studies.
FAU - Al-Horani, Rami A
AU  - Al-Horani RA
AD  - Department of Medicinal Chemistry and Institute for Structural Biology and Drug 
      Discovery, Virginia Commonwealth University , 800 E. Leigh Street, Suite 212, 
      Richmond, Virginia 23219, United States.
FAU - Desai, Umesh R
AU  - Desai UR
LA  - eng
GR  - P01 HL107152/HL/NHLBI NIH HHS/United States
GR  - R01 HL090586/HL/NHLBI NIH HHS/United States
GR  - HL090586/HL/NHLBI NIH HHS/United States
GR  - HL107152/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140529
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Anticoagulants)
RN  - 0 (Enzyme Precursors)
RN  - 0 (Glucosides)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Sulfuric Acid Esters)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.21.27 (Factor XIa)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Allosteric Regulation
MH  - Anticoagulants/*chemistry/pharmacology
MH  - Catalytic Domain
MH  - Enzyme Precursors/chemistry
MH  - Factor XIa/*antagonists & inhibitors/chemistry
MH  - Glucosides/*chemistry/pharmacology
MH  - Heparin/chemistry
MH  - Humans
MH  - Kinetics
MH  - Models, Molecular
MH  - Protein Binding
MH  - Recombinant Proteins/chemistry
MH  - Structure-Activity Relationship
MH  - Sulfuric Acid Esters/*chemistry/pharmacology
MH  - Thermodynamics
MH  - Thrombin/antagonists & inhibitors
PMC - PMC4216218
EDAT- 2014/05/23 06:00
MHDA- 2014/08/21 06:00
PMCR- 2015/05/20
CRDT- 2014/05/22 06:00
PHST- 2014/05/22 06:00 [entrez]
PHST- 2014/05/23 06:00 [pubmed]
PHST- 2014/08/21 06:00 [medline]
PHST- 2015/05/20 00:00 [pmc-release]
AID - 10.1021/jm500311e [doi]
PST - ppublish
SO  - J Med Chem. 2014 Jun 12;57(11):4805-18. doi: 10.1021/jm500311e. Epub 2014 May 29.