Modified-peptide inhibitors of amyloid beta-peptide polymerization.
Cellular toxicity resulting from nucleation-dependent polymerization of amyloid beta-peptide (Abeta) is considered to be a major and possibly the primary component of Alzheimer's disease (AD). Inhibition of Abeta polymerization has thus been identified as a target for the development of therapeutic agents for the treatment of AD. The intrinsic affinity of Abeta for itself suggested that Abeta-specific interactions could be adapted to the development of compounds that would bind to Abeta and prevent it from polymerizing. Abeta-derived peptides of fifteen residues were found to be inhibitory of Abeta polymerization. The activity of these peptides was subsequently enhanced through modification of their amino termini with specific organic reagents. Additional series of compounds prepared to probe structural requirements for activity allowed reduction of the size of the inhibitors and optimization of the Abeta-derived peptide portion to afford a lead compound, cholyl-Leu-Val-Phe-Phe-Ala-OH (PPI-368), with potent polymerization inhibitory activity but limited biochemical stability. The corresponding all-D-amino acyl analogue peptide acid (PPI-433) and amide (PPI-457) retained inhibitory activity and were both stable in monkey cerebrospinal fluid for 24 h.
Findeis
M A
MA
PRAECIS Pharmaceuticals Incorporated, Cambridge, Massachusetts, 02139-1572, USA. mfindeis@ppi.com
Musso
G M
GM
Arico-Muendel
C C
CC
Benjamin
H W
HW
Hundal
A M
AM
Lee
J J
JJ
Chin
J
J
Kelley
M
M
Wakefield
J
J
Hayward
N J
NJ
Molineaux
S M
SM
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000737:chemistry* / Q000493:pharmacokinetics; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; D011108:Polymers