Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis.
The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.
Pepys
M B
MB
Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, London NW3 2PF, UK. m.pepys@rfc.ucl.ac.uk
Herbert
J
J
Hutchinson
W L
WL
Tennent
G A
GA
Lachmann
H J
HJ
Gallimore
J R
JR
Lovat
L B
LB
Bartfai
T
T
Alanine
A
A
Hertel
C
C
Hoffmann
T
T
Jakob-Roetne
R
R
Norcross
R D
RD
Kemp
J A
JA
Yamamura
K
K
Suzuki
M
M
Taylor
G W
GW
Murray
S
S
Thompson
D
D
Purvis
A
A
Kolstoe
S
S
Wood
S P
SP
Hawkins
P N
PN
D000686:Amyloidosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
D002264:Carboxylic Acids; D003432:Cross-Linking Reagents; D011759:Pyrrolidines; C455899:R-1-(6-(R-2-carboxypyrrolidin-1-yl)-6-oxohexanoyl)pyrrolidine-2-carboxylic acid; D000683:Serum Amyloid P-Component; D002118:Calcium